Compounds

ABSTRACT

Novel substituted pyrimido[4,5-d]pyrimidin-2-one compounds and compositions for use in therapy as CSBP/p38 kinase inhibitors.

This application is a continuation of U.S. Ser. No. 11/613,517, filed 20Dec. 2006 which is a continuation of U.S. Ser. No. 10/220,103 filed 28Aug. 2002, now U.S. Pat. No. 7,235,551, 26 Jun. 2007, which is thenational stage entry of PCT/US01/06688, filed 2 Mar. 2001, and claimsbenefit of priority of U.S. Provisional Application 60/186,419 filed 2Mar. 2000.

FIELD OF THE INVENTION

This invention relates to a novel group of1,5-disubstituted-3,4-dihydro-1H -pyrimido[4,5-d]pyrimidin-2-onecompounds, processes for the preparation thereof, the use thereof intreating CSBP/p38 kinase mediated diseases and pharmaceuticalcompositions for use in such therapy.

BACKGROUND OF THE INVENTION

Intracellular signal transduction is the means by which cells respond toextracellular stimuli. Regardless of the nature of the cell surfacereceptor (e.g. protein tyrosine kinase or seven-transmembrane G-proteincoupled), protein kinases and phosphatases along with phospholipases arethe essential machinery by which the signal is further transmittedwithin the cell [Marshall, J. C. Cell, 80, 179-278 (1995)]. Proteinkinases can be categorized into five classes with the two major classesbeing, tyrosine kinases and serine/threonine kinases depending uponwhether the enzyme phosphorylates its substrate(s) on specifictyrosine(s) or serine/threonine(s) residues [Hunter, T., Methods inEnzymology (Protein Kinase Classification) p. 3, Hunter, T.; Sefton, B.M.; eds. vol. 200, Academic Press; San Diego, 1991].

For most biological responses, multiple intracellular kinases areinvolved and an individual kinase can be involved in more than onesignaling event. These kinases are often cytosolic and can translocateto the nucleus or the ribosomes where they can affect transcriptionaland translational events, respectively. The involvement of kinases intranscriptional control is presently much better understood than theireffect on translation as illustrated by the studies on growth factorinduced signal transduction involving MAP/ERK kinase [Marshall, C. J.Cell, 80, 179 (1995); Herskowitz, I. Cell, 80, 187 (1995); Hunter, T.Cell, 80, 225 (1995); Seger, R., and Krebs, E. G. FASEB J., 726-735(1995)].

While many signaling pathways are part of cell homeostasis, numerouscytokines (e.g., IL-1 and TNF) and certain other mediators ofinflammation (e.g., COX-2, and iNOS) are produced only as a response tostress signals such as bacterial lipopolysaccharide (LPS). The firstindications suggesting that the signal transduction pathway leading toLPS-induced cytokine biosynthesis involved protein kinases came fromstudies of Weinstein [Weinstein, et al., J. Immunol. 151, 3829 (1993)]but the specific protein kinases involved were not identified. Workingfrom a similar perspective, Han [Han, et al., Science 265, 808 (1994)]identified murine p38 as a kinase which is tyrosine phosphorylated inresponse to LPS. Definitive proof of the involvement of the p38 kinasein LPS-stimulated signal transduction pathway leading to the initiationof proinflammatory cytokine biosynthesis was provided by the independentdiscovery of p38 kinase by Lee [Lee; et al., Nature, 372, 739 (1994)] asthe molecular target for a novel class of anti-inflammatory agents. Thediscovery of p38 (termed by Lee as CSBP 1 and 2) provided a mechanism ofaction of a class of anti-inflammatory compounds for which SK&F 86002was the prototypic example. These compounds inhibited IL-1 and TNFsynthesis in human monocytes at concentrations in the low uM range [Lee,et al., Int. J. Immunopharmac. 10(7), 835 (1988)] and exhibited activityin animal models which are refractory to cyclooxygenase inhibitors [Lee;et al., Annals N.Y. Acad. Sci., 696, 149 (1993)].

It is now firmly established that CSBP/p38 is a one of several kinasesinvolved in a stress-response signal transduction pathway, which isparallel to and largely independent of the analogous mitogen-activatedprotein kinase (MAP) kinase cascade. Stress signals, including LPS,pro-inflammatory cytokines, oxidants, UV light and osmotic stress,activate kinases upstream from CSBP/p38 which in turn phosphorylateCSBP/p38 at threonine 180 and tyrosine 182 resulting in CSBP/p38activation. MAPKAP kinase-2 and MAPKAP kinase-3 have been identified asdownstream substrates of CSBP/p38 which in turn phosphorylate heat shockprotein Hsp 27 (FIG. 1). Additional downstream substrates known to bephosphorylated by p38 include kinases (Mnk 1/2, MSK 1/2 and PRAK) andtranscription factors (CHOP, MEF2, ATF2 and CREB). While many of thesignaling pathways required for cytokine biosynthesis remain unknown itappears clear that many of the substrates for p38 listed above areinvolved. [Cohen, P. Trends Cell Biol., 353-361 (1997) and Lee, J. C. etal, Pharmacol. Ther. vol. 82, nos. 2-3, pp. 389-397, 1999].

What is known, however, is that in addition to inhibiting IL-1 and TNF,CSBP/p38 kinase inhibitors (SK&F 86002 and SB 203580) also decrease thesynthesis of a wide variety of pro-inflammatory proteins including,IL-6, IL-8, GM-CSF and COX-2. Inhibitors of CSBP/p38 kinase have alsobeen shown to suppress the TNF-induced expression of VCAM-1 onendothelial cells, the TNF-induced phosphorylation and activation ofcytosolic PLA2 and the IL-1-stimulated synthesis of collagenase andstromelysin. These and additional data demonstrate that CSBP/p38 isinvolved not only cytokine synthesis, but also in cytokine signaling[CSBP/P38 kinase reviewed in Cohen, P. Trends Cell Biol., 353-361(1997)].

Interleukin-1 (IL-1) and Tumor Necrosis Factor (TNF) are biologicalsubstances produced by a variety of cells, such as monocytes ormacrophages. IL-1 has been demonstrated to mediate a variety ofbiological activities thought to be important in immunoregulation andother physiological conditions such as inflammation [See, e.g.,Dinarello et al., Rev. Infect. Disease, 6, 51 (1984)]. The myriad ofknown biological activities of IL-1 include the activation of T helpercells, induction of fever, stimulation of prostaglandin or collagenaseproduction, neutrophil chemotaxis, induction of acute phase proteins andthe suppression of plasma iron levels.

There are many disease states in which excessive or unregulated IL-1production is implicated in exacerbating and/or causing the disease.These include rheumatoid arthritis, osteoarthritis, endotoxemia and/ortoxic shock syndrome, other acute or chronic inflammatory disease statessuch as the inflammatory reaction induced by endotoxin or inflammatorybowel disease; tuberculosis, atherosclerosis, muscle degeneration,cachexia, psoriatic arthritis, Reiter's syndrome, rheumatoid arthritis,gout, traumatic arthritis, rubella arthritis, and acute synovitis.Recent evidence also links IL-1 activity to diabetes and pancreatic βcells [review of the biological activities which have been attributed toIL-1 Dinarello, J. Clinical Immunology, 5 (5), 287-297 (1985)].

Excessive or unregulated TNF production has been implicated in mediatingor exacerbating a number of diseases including rheumatoid arthritis,rheumatoid spondylitis, osteoarthritis, gouty arthritis and otherarthritic conditions; sepsis, septic shock, endotoxic shock, gramnegative sepsis, toxic shock syndrome, adult respiratory distresssyndrome, cerebral malaria, chronic pulmonary inflammatory disease,silicosis, pulmonary sarcoisosis, bone resorption diseases, reperfusioninjury, graft vs. host reaction, allograft rejections, fever andmyalgias due to infection, such as influenza, cachexia secondary toinfection or malignancy, cachexia, secondary to acquired immunedeficiency syndrome (AIDS), AIDS, ARC (AIDS related complex), keloidformation, scar tissue formation, Crohn's disease, ulcerative colitis,or pyresis.

Interleukin-8 (IL-8) is a chemotactic factor produced by several celltypes including mononuclear cells, fibroblasts, endothelial cells, andkeratinocytes. Its production from endothelial cells is induced by IL-1,TNF, or lipopolysachharide (LPS). IL-8 stimulates a number of functionsin vitro. It has been shown to have chemoattractant properties forneutrophils, T-lymphocytes, and basophils. In addition it induceshistamine release from basophils from both normal and atopic individualsas well as lysozomal enzyme release and respiratory burst fromneutrophils. IL-8 has also been shown to increase the surface expressionof Mac-1 (CD11b/CD18) on neutrophils without de novo protein synthesis,this may contribute to increased adhesion of the neutrophils to vascularendothelial cells. Many diseases are characterized by massive neutrophilinfiltration. Conditions associated with an increased in IL-8 production(which is responsible for chemotaxis of neutrophil into the inflammatorysite) would benefit by compounds, which are suppressive of IL-8production.

IL-1 and TNF affect a wide variety of cells and tissues and thesecytokines as well as other leukocyte derived cytokines are important andcritical inflammatory mediators of a wide variety of disease states andconditions. The inhibition of these cytokines is of benefit incontrolling, reducing and alleviating many of these disease states.

Inhibition of signal transduction via CSBP/p38, which in addition toIL-1, TNF and IL-8 described above is also required for the synthesisand/or action of several additional pro-inflammatory proteins (i.e.,IL-6, GM-CSF, COX-2, collagenase and stromelysin), is expected to be ahighly effective mechanism for regulating the excessive and destructiveactivation of the immune system. This expectation is supported by thepotent and diverse anti-inflammatory activities described for CSBP/p38kinase inhibitors [Badger, et al., J. Pharm. Exp. Thera. 279 (3):1453-1461. (1996); Griswold, et al, Pharmacol. Comm. 7, 323-229 (1996)].

The field of patents and patent applications disclosing compounds usefulfor the treatment of p38 mediated diseases has expanded rapidly over thelast several years. In most instances the central core molecule has beenan imidazole, oxazole or pyrazole derivative, such as those disclosed inWO 93/14081; WO 93/14082; WO 95/02591; WO 95/13067; WO 95/31451; WO99/58523; WO 98/56377; WO 97/16442; WO 99/57101; WO 00/39116; and WO00/31063. Newer ring systems include cycloalkenyl, pyrimidine, pyrazine,and triazole cores such as WO 00/25791; WO 98/24782; WO 99/17776; WO00/10563; WO 00/25791; and WO 00/35911; and multi ring systems, such asWO 99/64400; WO 98/22457; WO 00/20402; WO 00/12497; WO 99/61426 and WO99/58502.

However, despite all of this research effort there still remains a needfor treatments in this field, for compounds which inhibit theCSBP/p38/RK kinase, and are useful in the treatment of disease mediatedthereby.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 demonstrates the p38 kinase cascade.

FIG. 2 demonstrates a Citric Acid Induced Cough Model.

FIG. 3 demonstrates an Antigen- or LTD4-Induced Hypertussive Model inthe Guinea Pig

FIG. 4 demonstrates Effects of Dextromethorphan or Codeine On CitricAcid-Induced Cough in Guinea Pigs.

SUMMARY OF THE INVENTION

This invention relates to the novel compounds of Formulas (I) to (V) and(Ia) to (Va), and pharmaceutical compositions comprising a compound ofFormula (I) to (V) and (Ia) to (Va), and a pharmaceutically acceptablediluent or carrier.

This invention relates to a method of treating, including prophylaxis,of a CSBP/RK/p38 kinase mediated disease in a mammal in need thereof,which comprises administering to said mammal an effective amount of acompound of Formulas (I) to (V) and (Ia) to (Va).

Accordingly, the present invention provides a compound of Formula (I):

wherein

-   R₁ is an aryl or heteroaryl ring, which ring is optionally    substituted;-   R₂ is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylC₁₋₁₀    alkyl, aryl, arylC₁₋₁₀alkyl, heteroaryl, heteroarylC₁₋₁₀ alkyl,    heterocyclic, or a heterocyclylC₁₋₁₀ alkyl moiety; and wherein each    of these moieties, excluding hydrogen, are optionally substituted;-   R₃ is a C₁₋₁₀ alkyl, C₃₋₇cycloalkyl, C₃₋₇ cycloalkylC₁₋₁₀ alkyl,    arylC₁₋₁₀ alkyl, heteroarylC₁₋₁₀ alkyl, or heterocyclylC₁₋₁₀ alkyl    moiety; and wherein each of these moieties are optionally    substituted;-   X is R₂, OR₂, S(O)_(m)R₂ or (CH₂)_(n)NR₂R₁₄, or (CH₂)_(n)NR₂R₄;-   n is 0 or an integer having a value of 1 to 10;-   m is 0 or an integer having a value of 1 or 2;-   R₄ and R₁₄ are each independently selected from hydrogen, optionally    substituted C₁₋₄ alkyl, optionally substituted aryl, or an    optionally substituted arylC₁₋₄alkyl, or R₄ and R₁₄ together with    the nitrogen to which they are attached form a heterocyclic ring of    5 to 7 members, which ring optionally contains an additional    heteroatom selected from oxygen, sulfur or NR₉, and which ring may    be optionally substituted;-   R₆ is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, heterocyclyl,    heterocyclylC₁₋₁₀alkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl or a    heteroarylC₁₋₁₀ alkyl moiety; and wherein each of these moieties,    excluding hydrogen, may be optionally substituted;-   R₉ is hydrogen, C(Z)R₆, optionally substituted C₁₋₁₀alkyl,    optionally substituted aryl or optionally substituted arylC₁₋₄    alkyl;-   Z is oxygen or sulfur;    or a pharmaceutically acceptable salt thereof.

Another aspect of the present invention is the novel compounds ofFormula (II) represented by the structure:

wherein

-   R₁ is an aryl or a heteroaryl ring, which ring may be optionally    substituted;-   R₂ is hydrogen, C₁₋₁₀alkyl, C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁ ₋₁₀    alkyl, aryl, arylC₁₋₁₀alkyl, heteroaryl, heteroarylC₁₋₁₀alkyl,    heterocyclic, or a heterocyclylC₁₋₁₀ alkyl moiety; and wherein each    of these moieties, excluding hydrogen, are optionally substituted;-   R₃ is an C₁₋₁₀alkyl, C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₁₀ alkyl,    aryl, arylC₁₋₁₀alkyl, heteroaryl, heteroarylC₁₋₁₀ alkyl,    heterocyclic, or a heterocyclylC₁₋₁₀ alkyl moiety; and wherein each    of these moieties are optionally substituted;-   Y is CR_(b), C(O), N(R_(d)), oxygen, or S(O)_(m);-   R_(b) is hydrogen, C₁₋₂ alkyl, NR_(C), hydroxy, thio, C₁₋₂ alkoxy,    or S(O)_(m)C₁₋₂ alkyl;-   R_(c) is hydrogen or C₁₋₂ alkyl;-   R_(d) is hydrogen or C₁₋₂ alkyl;-   X is R₂, OR₂, S(O)_(m)R₂, (CH₂)_(n)NR₂R₁₄, or (CH₂)_(n)NR₂R₄;-   m is 0 or an integer having a value of 1 or 2;-   n is 0 or an integer having a value of 1 to 10;-   R₄ and R₁₄ are each independently selected from hydrogen, optionally    substituted C₁₋₄ alkyl, optionally substituted aryl, or an    optionally substituted arylC₁₋₄alkyl, or R₄ and R₁₄ together with    the nitrogen which they are attached form a heterocyclic ring of 5    to 7 members which ring optionally contains an additional heteroatom    selected from oxygen, sulfur or NR₉, and which ring may be    optionally substituted;-   R₆ is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, heterocyclyl,    heterocyclyl C₁₋₁₀alkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl or a    heteroarylC₁₋₁₀alkyl; and wherein each of these moieties, excluding    hydrogen, may be optionally substituted;-   R₉ is hydrogen, C(Z)R₆ or optionally substituted C₁₋₁₀alkyl,    optionally substituted aryl or optionally substituted aryl-C₁₋₄    alkyl;-   Z is oxygen or sulfur;    or a pharmaceutically acceptable salt thereof.

Another aspect of the present invention are the novel compounds ofFormula (III) represented by the structure:

wherein

-   R₁ is an aryl, or a heteroaryl ring, which ring may be optionally    substituted;-   R₂ is a heterocyclic or heterocyclicC₁₋₁₀ alkyl ring, which is ring    is optionally substituted;-   R_(2′) is a heterocyclic, heterocyclicC₁₋₁₀ alkyl, aryl, or    heteroaryl ring, which ring is optionally substituted;-   R₃ is an aryl or heteroaryl ring, which ring is optionally    substituted;-   X is R_(2′), OR₂, S(O)_(m)R₂ or (CH₂)_(n)NR₂R₁₄, or (CH₂)_(n)NR₂R₄;    provided that when X is (CH₂)_(n)NR₄R₁₄, then R₄R₁₄ must form the    optionally substituted cyclized ring optionally comprising an    oxygen, sulfur or nitrogen moiety;-   n is 0 or an integer having a value of 1 to 10;-   m is 0 or an integer having a value of 1 or 2;-   R₄ and R₁₄ are independently selected from hydrogen, optionally    substituted C₁₋₄ alkyl, optionally substituted aryl, or optionally    substituted arylC₁₋₄ alkyl; or R₄ and R₁₄ together with the nitrogen    which they are attached form a heterocyclic ring of 5 to 7 members    which ring optionally contains an additional heteroatom selected    from oxygen, sulfur or NR₉, and which ring is optionally    substituted;-   R₆ is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, heterocyclyl,    heterocyclyl C₁₋₁₀alkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl or a    heteroarylC₁₋₁₀ alkyl moiety;-   and wherein each of these moieties, excluding hydrogen, is    optionally substituted;-   R₉ is hydrogen, C(Z)R₆, optionally substituted C₁₋₁₀alkyl,    optionally substituted aryl, or optionally substituted arylC₁₋₄    alkyl;-   Z is oxygen or sulfur;    or a pharmaceutically acceptable salt thereof.

Another aspect of the present invention are the novel compounds ofFormula (IV) represented by the structures:

wherein

-   R₁ is an aryl or a heteroaryl ring, which ring is optionally    substituted;-   R₂ is hydrogen, C₁₋₁₀alkyl, C₃₋₇ cycloalkyl, C₃₋₇    cycloalkylC₁₋₁₀alkyl, aryl, arylC₁₋₁₀alkyl, heteroaryl,    heteroarylC₁₋₁₀alkyl, heterocyclic, or a heterocyclylC₁₋₁₀ alkyl    moiety; and wherein each of these moieties, excluding hydrogen, are    optionally substituted;-   R₃ is a CR₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylC₁₋₁₀alkyl,    aryl, arylC₁₋₁₀alkyl, heteroaryl, heteroarylC₁₋₁₀ alkyl,    heterocyclic, or a heterocyclylC₁₋₁₀ alkyl moiety; and wherein each    of these moieties are optionally substituted;-   Y is a bond, CR_(b), C(O), N(R_(d)), oxygen, or S(O)_(m);-   R_(b) is hydrogen, C₁₋₂alkyl, NR_(C), hydroxy, thio, C₁₋₂alkoxy,    S(O)_(m)C₁₋₁₂alkyl;-   R_(c) is hydrogen or C₁₋₂alkyl;-   R_(d) is hydrogen or C₁₋₂alkyl;-   X is R₂, OR₂, S(O)_(m)R₂ or (CH₂)_(n)NR₂R₁₄, or (CH₂)_(n)NR₂R₄;-   n is 0 or an integer having a value of 1 to 10;-   m is 0 or an integer having a value of 1 or 2;-   R₄ and R₁₄ are each independently selected from hydrogen, optionally    substituted C₁₋₄ alkyl, optionally substituted aryl, or optionally    substituted arylC₁₋₄ alkyl, or R₄ and R₁₄ together with the nitrogen    which they are attached form a heterocyclic ring of 5 to 7 members    which ring optionally contains an additional heteroatom selected    from oxygen, sulfur or NR₉, and which ring is optionally    substituted;-   R₆ is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, heterocyclyl,    heterocyclyl C₁₋₁₀ alkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl or a    heteroarylC₁₋₁₀ alkyl moiety, and wherein each of these moieties,    excluding hydrogen, is optionally substituted;-   R₉ is hydrogen, C(Z)R₆, optionally substituted C₁₋₁₀ alkyl,    optionally substituted aryl or an optionally substituted aryl-C₁₋₄    alkyl;-   Z is oxygen or sulfur;    or a pharmaceutically acceptable salt thereof.

Accordingly, the present invention also provides for a compound ofFormula (V):

wherein

-   X is R₂, OR₂, S(O)_(m)R₂ or (CH₂)_(n)NR₄R₁₄, or (CH₂)_(n)NR₂R₄;-   n is 0 or an integer having a value of 1 to 10;-   m is 0 or an integer having a value of 1 or 2;-   R₁ is an optionally substituted aryl ring;-   R₂ is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylC₁₋₁₀    alkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl, heteroarylC₁₋₁₀ alkyl,    heterocyclic, or a heterocyclylC₁₋₁₀ alkyl moiety; and wherein each    of these moieties, excluding hydrogen are optionally substituted;-   R₃ is an optionally substituted aryl ring;-   R₄ and R₁₄ are each independently selected from hydrogen, optionally    substituted C₁₋₄ alkyl, optionally substituted aryl, or optionally    substituted aryl-C₁₋₄ alkyl, or R₄ and R₁₄ together with the    nitrogen which they are attached form a heterocyclic ring of 5 to 7    members which ring optionally contains an additional heteroatom    selected from oxygen, sulfur or NR₉, and which ring is optionally    substituted;-   R₆ is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, heterocyclyl,    heterocyclyl C₁₋₁₀ alkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl or a    heteroarylC₁₋₁₀ alkyl moiety; and wherein each of these moieties,    excluding hydrogen, may be optionally substituted;-   R₉ is hydrogen, C(Z)R₆, optionally substituted C₁₋₁₀ alkyl,    optionally substituted aryl or an optionally substituted arylC₁₋₄    alkyl;-   Z is oxygen or sulfur;    or a pharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to the novel compounds of Formulas (I)to (V), and Formula (Ia) to (Va), or a pharmaceutically acceptable saltthereof, pharmaceutical compositions comprising a compound of Formula(I) to (V), and (Ia) to (Va), or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier or diluent thereof,and also to the use of these compounds in the treatment or prophylaxisof CSBP mediated diseases in a mammal in need thereof.

As will be readily recognized, the difference between compounds ofFormula (I) to (V) and (Ia) to (Va) lie in the unsaturation of thepyrimidine-2-one ring. The respective R₁, R₂, X and R₃ terms are thesame for both groups within a formula set, i.e. I and Ia. For purposesherein, everything applicable to Formula (I) is also applicable toFormula (Ia), Formula (II) and (Ia), Formula (III) and (IIIa), andFormula (V) and (Va) unless otherwise indicated. It should be noted thatcompounds of Formula (I), (II), (III) and (V) are all subsets ofcompounds of Formula (IV).

More specifically, the present invention is directed to the novelcompounds of Formulas (I) and (Ia), or pharmaceutically acceptable saltsthereof.

Suitably, for these compounds of Formula (I) and (Ia), R₁ is an aryl, ora heteroaryl ring, which ring is optionally substituted. The ring may besubstituted one or more times, in any ring, suitably 1 to 4 times,preferably 1 to 2 times, independently, by halogen, C₁₋₄ alkyl,halo-substituted-C₁₋₄ alkyl, cyano, nitro, (CR₁₀R₂₀)_(v)NR₄R₁₄,(CR₁₀R₂₀)_(v)C(Z)NR₄R₁₄, (CR₁₀R₂₀)_(v)C(Z)OR₈, (CR₁₀R₂₀)_(v)COR_(a),(CR₁₀R₂₀)_(v)C(O)H, S(O)_(m)R₅, (CR₁₀R₂₀)_(v)OR₈, ZC(Z)R₁₁, NR₁₀C(Z)R₁₁,or NR₁₀S(O)₂R₇. Preferably the ring is an aryl ring, more preferablyphenyl, which ring is unsubstituted or substituted one or more times byhalogen, preferably chloro or fluoro, or alkyl, preferably methyl.Suitably, the ring is substituted in the 4-position, and ifdi-substituted, it is in the 2-, 4-position of the phenyl ring.

Suitably m is 0 or an integer having a value of 1 or 2.

Suitably, v is 0 or an integer having a value of 1 or 2.

Suitably, Z is oxygen or sulfur.

Suitably, R_(a) is C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, C₃₋₇ cycloalkyl, C₅₋₇ cycloalkenyl, aryl,arylC₁₋₄ alkyl, heteroaryl, heteroarylC₁₋₄ alkyl, heterocyclyl,heterocyclylC₁₋₄ alkyl, (CR₁₀R₂₀)_(v)OR₇, (CR₁₀R₂₀)_(v)S(O)_(m)R₇,(CR₁₀R₂₀)_(v)NHS(O)₂R₇, or (CR₁₀R₂₀)_(v)NR₄R₁₄; and wherein the alkyl,cycloalkyl, cycloalkenyl, aryl, arylalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, and heteroaryl alkyl moieties may beoptionally substituted.

Suitably, R₄ and R₁₄ are each independently selected from hydrogen,optionally substituted C₁₋₆ alkyl, optionally substituted aryl, or anoptionally substituted aryl-C₁₋₆ alkyl, or R₄ and R₁₄ together with thenitrogen to which they are attached in NR₄R₁₄ substituent may form aheterocyclic ring of 5 to 7 members which ring optionally contains anadditional heteroatom selected from oxygen, sulfur or NR₉, and whichring may be optionally substituted.

Suitably, R₅ is hydrogen, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl orNR₄R₁₄, excluding the moieties SR₅ (wherein m is 0) being SNR₄R₁₄,S(O)₂R₅ being SO₂H (wherein m is 2) and S(O)R₅ being SOH, (wherein m is1).

Suitably, R₆ is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, heterocyclyl,heterocyclyl C₁₋₁₀ alkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl or aheteroarylC₁ ₋₁₀ alkyl moiety, and wherein each these moieties may beoptionally substituted. It is recognized herein that hydrogen can not besubstituted and is therefore excluded.

Suitably, R₇ is C₁₋₆alkyl, aryl, arylC₁₋₆alkyl, heterocyclic,heterocyclylC₁₋₆alkyl, heteroaryl, or a heteroarylC₁₋₆alkyl moiety; andwherein each of these moieties may be optionally substituted.

Suitably, R₈ is hydrogen, C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl,C₂₋₄alkenyl, C₂₋₄ alkynyl, C₃₋₇ cycloalkyl, C₅₋₇ cycloalkenyl, aryl,arylC₁₋₄ alkyl, heteroaryl, heteroarylC₁₋₄ alkyl, heterocyclyl,heterocyclylC₁₋₄ alkyl, (CR₁₀R₂₀)_(t)OR₇, (CR₁₀R₂₀)_(t)S(O)_(m)R₇,(CR₁₀R₂₀)_(t)NHS(O)₂R₇, or (CR₁₀R₂₀)_(t)NR₄R₁₄; and wherein the alkyl,cycloalkyl, cycloalkenyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroaryl alkyl moieties, may be optionallysubstituted.

Suitably, t is an integer having a value of 1 to 3.

Suitably, R₉ is hydrogen, C(Z)R₆, optionally substituted C₁₋₁₀ alkyl,optionally substituted aryl, or optionally substituted aryl-C₁₋₄ alkyl.

Suitably, R₁₀ and R₂₀ are each independently selected from hydrogen orC₁₋₄ alkyl.

Suitably, R₁₁ is C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, C₂₋₄ alkenyl,C₂₋₄alkynyl, C₃₋₇ cycloalkyl, C₅₋₇ cycloalkenyl, aryl, arylC₁₋₄ alkyl,heteroaryl, heteroarylC₁₋₄ alkyl, heterocyclyl, heterocyclylC₁₋₄ alkyl,(CR₁₀R₂₀)_(t)OR₇, (CR₁₀R₂₀)_(t)S(O)_(m)R₇, (CR₁₀R₂₀)_(t)NHS(O)₂R₇, or(CR₁₀R₂₀)_(v)NR₄R₁₄; and wherein the alkyl, cycloalkyl, cycloalkenyl,aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, andheteroaryl alkyl moieties may be optionally substituted.

Suitably, R₃ is a C₁₋₁₀alkyl, C₃₋₇ cycloalkyl, C₃₋₇cycloalkylC₁₋₁₀alkyl, arylC₁₋₁₀ alkyl, heteroarylC₁₋₁₀ alkyl, or aheterocyclylC₁₋₁₀ alkyl moiety, and wherein each of these moieties maybe optionally substituted, independently, one or more times, suitably 1to 4 times, preferably 1 to 2 times, (in any applicable ring) with C₁₋₁₀alkyl, halosubstituted C₁₋₁₀ alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₁₀alkyl, C₅₋₇ cycloalkenyl,C₅₋₇cycloalkenylC₁₋₁₀ alkyl, halogen, (CR₁₀R₂₀)_(n)OR₆, (CR₁₀R₂₀)_(n)SH,(CR₁₀R₂₀)_(n)S(O)_(m)R₇, (CR₁₀R₂₀)_(n)NHS(O)₂R₇, (CR₁₀R₂₀)_(n)NR₄R₁₄(CR₁₀R₂₀)_(n)CN, (CR₁₀R₂₀)_(n) S(O)₂NR₄R₁₄, (CR₁₀R₂₀)_(n)C(Z)R₆,(CR₁₀R₂₀)_(n)OC(Z)R₆, (CR₁₀R₂₀)_(n)C(Z)OR₆, (CR₁₀R₂₀)_(n)C(Z)NR₄R₁₄,(CR₁₀R₂₀)_(n)NR₁₀C(Z)R₆, (CR₁₀R₂₀)_(n)NR₁₀C(═NR₁₀)NR₄R₁₄,(CR₁₀R₂₀)_(n)OC(Z)NR₄R₁₄, (CR₁₀R₂₀)_(n)NR₁₀C(Z)NR₄R₁₄, or(CR₁₀R₂₀)_(n)NR₁₀C(Z)OR₇.

Preferably, R₃ is an optionally substituted C₃₋₇ cycloalkyl, orarylC₁₋₁₀-alkyl, more preferably optionally substituted cyclohexyl,benzyl or phenethyl. Preferably, the ring is unsubstituted orsubstituted one or more times, independently with halogen, morepreferably fluorine, or chlorine, or alkyl, such as methyl. The ring ispreferably substituted in the 2-position or di-substituted in the 2-,6-position, more preferably with fluorine, methyl, difluoro, ordimethyl.

Suitably, n is 0, or an integer having a value of 1 to 10.

Suitably, R₂ is hydrogen, C₁₋₁₀alkyl, C₃₋₇ cycloalkyl,C₃₋₇cycloalkylC₁₋₁₀alkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl,heteroarylC₁₋₁₀ alkyl, heterocyclic, or a heterocyclylC₁₋₁₀ alkylmoiety; and wherein these moieties, excluding hydrogen, may beoptionally substituted one or more times, suitably 1 to 4 times,independently (in any applicable ring) with C₁₋₁₀alkyl, halo-substitutedC₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₇cycloalkyl,C₃₋₇cycloalkylC₁ ₋₁₀alkyl, C₅₋₇ cycloalkenyl,C₅₋₇cycloalkenylC₁₋₁₀alkyl, halogen, (CR₁₀R₂₀)_(n)OR₆, (CR₁₀R₂₀)_(n)SH,(CR₁₀R₂₀)_(n)S(O)_(m)R₇, (CR₁₀R₂₀)_(n)NHS(O)₂R₇, (CR₁₀R₂₀)_(n)NR₄R₁₄,(CR₁₀R₂₀)_(n)CN, (CR₁₀R₂₀)_(n)S(O)₂NR₄R₁₄, (CR₁₀R₂₀)_(n)C(Z)R₆,(CR₁₀R₂₀)_(n)OC(Z)R₆, (CR₁₀R₂₀)_(n)C(Z)OR₆, (CR₁₀R₂₀)_(n)C(Z)NR₄R₁₄,(CR₁₀R₂₀)_(n)NR₁₀C(Z)R₆, (CR₁₀R₂₀)_(n)NR₁₀C(═NR₁₀)NR₄R₁₄,(CR₁₀R₂₀)_(n)OC(Z)NR₄R₁₄, (CR₁₀R₂₀)_(n)NR₁₀C(Z)NR₄R₁₄,(CR₁₀R₂₀)_(n)NR₁₀C(Z)OR₇, or a dioxyalkylene group of the formula—O—(CH₂)_(s)—O—, wherein s is 1 to 3, preferably s is 2 yielding a1,3-dioxyethylene moiety.

Suitably, X is R₂, OR₂, S(O)_(m)R₂ or (CH₂)_(n)NR₄R₁₄, or(CH₂)_(n)NR₂R₄.

Suitably, when X is the group OR₂, then R₂ is preferably an optionallysubstituted C₁₋₁₀ alkyl, an optionally substituted aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocyclic or heterocyclicalkyl moiety.Preferably, when the R₂ moiety is an alkyl it is a substituted orunsubstituted C₁₋₆ alkyl, Suitably, the alkyl substituents are asdefined herein, but are preferably, halogen, hydroxy, or NR₄R₁₄. When R₂is an optionally substituted heterocyclic, or heterocyclic alkyl ring,it is preferably a pyrrolidine, piperidine, piperazine, morpholine ringor a pyrrolidinyl alkyl, piperidinyl alkyl, piperazinyl alkyl, or amorpholinyl alkyl. More preferably, it is a piperidine or an alkylsubstituted piperidine, such as N-methyl piperidine.

Preferably, when X is the group S(O)_(m)R₂, R₂ is a substituted orunsubstituted alkyl, aryl or aryl alkyl.

Preferably, when X is the group (CH₂)_(n)NR₄R₁₄, n is preferably 0 or 1,more preferably 0. Preferably, if the R₄ and R₁₄ moiety cyclize the ringis a 5 or 6 membered ring, such as a pyrrolidine, piperidine,piperazine, or morpholine containing ring, which ring may be optionallysubstituted. Preferably when R₄ or R₁₄ is an optionally substitutedC₁₋₆alkyl, which chain may be a straight or branched chain, it issubstituted one or more times, suitably 1 to 4 times, preferably 1 or 2times, with halogen; hydroxy; hydroxy substituted C₁₋₁₀alkyl; C₁₋₁₀alkoxy; halosubstituted C₁₋₁₀ alkoxy; S(O)m C₁₋₄alkyl, wherein m is 0, 1or 2; NR₄R₁₄, such as amino or mono or -disubstituted C₁₋₆ alkyl orwherein the R₄R₁₄ can cyclize together with the nitrogen to which theyare attached to form a 5 to 7 membered ring which optionally contains anadditional heteroatom selected from O/N/S; C₃₋₇cycloalkyl;C₃₋₇cycloalkyl C₁₋₁₀ alkyl group; halosubstituted C₁₋₁₀ alkyl, suchCF₂CF₂H, or CF₃; optionally substituted aryl, such as phenyl, or anoptionally substituted arylalkyl, such as benzyl or phenethyl; andwherein these aryl or arylalkyl moieties may also themselves besubstituted one to two times by halogen; hydroxy; hydroxy substitutedalkyl; C₁₋₁₀ alkoxy; S(O)_(m) C₁₋₄ alkyl; amino, mono & di-substitutedC₁₋₆ alkyl amino, such as in the NR₄R₁₄ group; C₁₋₄ alkyl, or CF₃.

Preferably, the alkyl chain is branched, such as in t-butyl orisopropyl. More preferably the alkyl chain is substituted one or moretimes, independently by halogen, hydroxy, amino, or mono or di C₁₋₄alkyl substituted amino.

Preferably, when X is the group (CH₂)_(n)NR₂R₄, n is preferably 0 or 1,more preferably 0. The R₂ moiety is preferably, hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted heterocyclic,substituted or unsubstituted heterocyclic alkyl, substituted orunsubstituted heteroaryl, or substituted or unsubstitutedheteroarylalkyl. Such groups preferably include imidazole, tetrazole,pyrrolidine, piperidine, piperazine, morpholine, pyrrolidinyl alkyl,piperidinyl alkyl, piperazinyl alkyl, or morpholinyl alkyl.

Preferably, when X is the group R₂, then R₂ is preferably an optionallysubstituted heteroaryl, such as an imidazole, or tetrazole, or is anoptionally substituted heterocyclic ring, such as a pyrrolidine,piperidine, piperazine, or a morpholine ring

Another aspect of the present invention is directed to the compounds ofFormula (II) and (IIa).

Suitably, for compounds of Formula (II) and (IIa), R₁ is an aryl or aheteroaryl ring, which ring may be optionally substituted. The ring maybe substituted one or more times, in any ring, suitably 1 to 4 times,preferably 1 to 2 times, independently, by halogen, C₁₋₄ alkyl,halo-substituted-C₁₋₄ alkyl, cyano, nitro, (CR₁₀R₂₀)_(v)NR₄R₁₄,(CR₁₀R₂₀)_(v)C(Z)NR₄R₁₄, (CR₁₀R₂₀)_(v)C(Z)OR₈, (CR₁₀R₂₀)_(v)COR_(a),(CR₁₀R₂₀)_(v)C(O)H, S(O)_(m)R₅, (CR₁₀R₂₀)_(v)OR₈, ZC(Z)R₁₁, NR₁₀C(Z)R₁₁,or NR₁₀S(O)₂R₇. Preferably the ring is an aryl ring, more preferablyphenyl, which ring is unsubstituted or substituted one or more times byhalogen, preferably chloro or fluoro, or alkyl, preferably methyl.Suitably, the ring is substituted in the 4-position, and ifdi-substituted, it is in the 2-, 4-position of the phenyl ring.

Suitably, v is 0 or an integer having a value of 1 or 2.

Suitably, Z is oxygen or sulfur.

Suitably, R_(a) is C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, C₃₋₇ cycloalkyl, C₅₋₇ cycloalkenyl, aryl,arylC₁₋₄ alkyl, heteroaryl, heteroarylC₁₋₄ alkyl, heterocyclyl,heterocyclylC₁₋₄ alkyl, (CR₁₀R₂₀)_(v)OR₇, (CR₁₀R₂₀)_(v)S(O)_(m)R₇,(CR₁₀R₂₀)_(v)NHS(O)₂R₇, or (CR₁₀R₂₀)_(v)NR₄R₁₄; and wherein thecycloalkyl, C₅₋₇ cycloalkenyl, aryl, arylalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroarylalkyl moiety may beoptionally substituted.

Suitably, R₄ and R₁₄ is each independently selected from hydrogen,optionally substituted C₁₋₆ alkyl, optionally substituted aryl, oroptionally substituted aryl-C₁₋₆ alkyl, or R₄ and R₁₄ together with thenitrogen which they are attached form a heterocyclic ring of 5 to 7members which ring optionally contains an additional heteroatom selectedfrom oxygen, sulfur or NR₉, and which ring may be optionallysubstituted.

Suitably, R₅ is hydrogen, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl orNR₄R₁₄, excluding the moieties SR₅ (wherein m is 0) being SNR₄R₁₄,S(O)₂R₅ being SO₂H (wherein m is 2) and S(O)R₅ being SOH, (wherein m is1).

Suitably, R₆ is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, heterocyclyl,heterocyclyl C₁₋₁₀ alkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl or aheteroarylC₁ ₋₁₀ alkyl moiety, and wherein each of these moieties may beoptionally substituted (excluding hydrogen).

Suitably, R₇ is C₁₋₆alkyl, aryl, arylC₁₋₆alkyl, heterocyclic,heterocyclylC₁₋₆ alkyl, heteroaryl, or a heteroarylC₁₋₆alkyl; andwherein each of these moieties may be optionally substituted.

Suitably, R₈ is hydrogen, C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, C₃₋₇ cycloalkyl, C₅₋₇ cycloalkenyl, aryl, arylC₁₋₄ alkyl, heteroaryl, heteroarylC₁₋₄ alkyl, heterocyclyl,heterocyclylC₁₋₄ alkyl, (CR₁₀R₂₀)_(t)OR₇, (CR₁₀R₂₀)_(t)S(O)_(m)R₇,(CR₁₀R₂₀)_(t)NHS(O)₂R₇, or (CR₁₀R₂₀)_(t)NR₄R₁₄; and wherein the alkyl,cycloalkyl, cycloalkenyl, aryl, arylalkyl, heterocyclyl,heterocyclylalkyl heteroaryl, and heteroaryl alkyl moieties may beoptionally substituted.

Suitably, t is an integer having a value of 1 to 3.

Suitably, R₉ is hydrogen, C(Z)R₆, optionally substituted C₁₋₁₀ alkyl,optionally substituted aryl, or optionally substituted aryl-C₁₋₄ alkyl.

Suitably, R₁₀ and R₂₀ are each independently selected from hydrogen orC₁₋₄ alkyl.

Suitably, R₁₁ is C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, C₂₋₄ alkenyl,C₂₋₄alkynyl, C₃₋₇cycloalkyl, C₅₋₇ cycloalkenyl, aryl, arylC₁₋₄ alkyl,heteroaryl, heteroarylC₁₋₄ alkyl, heterocyclyl, heterocyclylC₁₋₄ alkyl,(CR₁₀R₂₀)_(t)OR₇, (CR₁₀R₂₀)_(t)S(O)_(m)R₇, (CR₁₀R₂₀)_(t)NHS(O)₂R₇, or(CR₁₀R₂₀)_(v)NR₄R₁₄; and wherein the alkyl, cycloalkyl, cycloalkenyl,aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, andheteroaryl alkyl moieties may be optionally substituted.

Suitably m is 0 or an integer having a value of 1 or 2.

Suitably, X is R₂, OR₂, S(O)_(m)R₂ or (CH₂)_(n)NR₄R₁₄, or(CH₂)_(n)NR₂R₄.

Suitably, Y is CR_(b), C(O), N(R_(d)), oxygen, or S(O)m.

Suitably, R_(b) is hydrogen, C₁₋₂ alkyl, NR_(C), hydroxy, thio, C₁₋₂alkoxy, S(O)_(m)C₁₋₂ alkyl.

Suitably, R_(c) is hydrogen or C₁₋₂ alkyl.

Suitably, R_(d) is hydrogen or C₁₋₂ alkyl.

Suitably, R₃ is a C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇cycloalkylC₁₋₁₀alkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl, heteroarylC₁₋₁₀alkyl, heterocyclic, or a heterocyclylC₁₋₁₀ alkyl moiety, and whereineach of these moieties may be optionally substituted, independently, oneor more times, suitably 1 to 4 times, preferably 1 to 2 times, (in anyapplicable ring) with C₁₋₁₀ alkyl, halo -substituted C₁₋₁₀ alkyl, C₂₋₁₀alkenyl, C₂₋₁₀ alkynyl, C₃₋₇ cycloalkyl, C₃ ₋₇cycloalkylC₁₋₁₀ alkyl,C₅₋₇ cycloalkenyl, C₅₋₇ cycloalkenyl C₁₋₁₀ alkyl, halogen,(CR₁₀R₂₀)_(n)OR₆, (CR₁₀R₂₀)_(n)SH, (CR₁₀R₂₀)_(n)S(O)_(m)R₇,(CR₁₀R₂₀)_(n)NHS(O)₂R₇, (CR₁₀R₂₀)_(n)NR₄R₁₄, (CR₁₀R₂₀)_(n)CN,(CR₁₀R₂₀)_(n)S(O)₂NR₄R₁₄, (CR₁₀R₂₀)_(n)C(Z)R₆, (CR₁₀R₂₀)_(n)OC(Z)R₆,(CR₁₀R₂₀)_(n)C(Z)OR₆, (CR₁₀R₂₀)_(n)C(Z)NR₄R₁₄, (CR₁₀R₂₀)_(n)NR₁₀C(Z)R₆,(CR₁₀R₂₀)_(n)NR₁₀C(═NR₁₀)NR₄R₁₄, (CR₁₀R₂₀)_(n)OC(Z)NR₄R₄,(CR₁₀R₂₀)_(n)NR₁₀C(Z)NR₄R₁₄, or (CR₁₀R₂₀)_(n)NR₁₀C(Z)OR₇.

Preferably, R₃ is an optionally substituted C₃₋₇ cycloalkyl, aryl, orarylC₁₋₁₀ alkyl, more preferably optionally substituted cyclohexyl,phenyl, benzyl or phenethyl. Preferably, the ring is unsubstituted orsubstituted one or more times, independently with halogen, morepreferably fluorine, or chlorine, or alkyl, such as methyl. The ring ispreferably substituted in the 2-position or di-substituted in the 2-,6-position, more preferably with fluorine, methyl, difluoro, ordimethyl.

Suitably, n is 0, or an integer having a value of 1 to 10.

Suitably, R₂ is hydrogen, C₁₋₁₀ alkyl, C₃₋₇cycloalkyl,C₃₋₇cycloalkylC₁₋₁₀alkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl,heteroarylC₁₋₁₀ alkyl, heterocyclic, or a heterocyclylC₁₋₁₀ alkylmoiety; and wherein each of these moieties, excluding hydrogen, may beoptionally substituted one or more times, suitably 1 to 4 times,independently (in any applicable ring), with C₁₋₁₀ alkyl,halo-substituted C₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₁₀alkyl, C₅₋₇ cycloalkenyl, C₅₋₇cycloalkenyl C₁₋₁₀ alkyl, halogen, (CR₁₀R₂₀)_(n)OR₆, (CR₁₀R₂₀)_(n)SH,(CR₁₀R₂₀)_(n)S(O)_(m)R₇, (CR₁₀R₂₀)_(n)NHS(O)₂R₇, (CR₁₀R₂₀)_(n)NR₄R₁₄,(CR₁₀R₂₀)_(n)CN, (CR₁₀R₂₀)_(n)S(O)₂N₄R₁₄, (CR₁₀R₂₀)_(n)C(Z)R₆,(CR₁₀R₂₀)_(n)OC(Z)R₆, (CR₁₀R₂₀)_(n)C(Z)OR₆, (CR₁₀R₂₀)_(n)C(Z)NR₄R₁₄,(CR₁₀R₂₀)_(n)NR₁₀C(Z)R₆, (CR₁₀R₂₀)_(n)NR₁₀C(═NR₁₀)NR₄R₁₄,(CR₁₀R₂₀)_(n)OC(Z)NR₄R₁₄, (CR₁₀R₂₀)_(n)NR₁₀C(Z)NR₄R₁₄,(CR₁₀R₂₀)_(n)NR₁₀C(Z)OR₇, or a dioxyalkylene group of the formula—O—(CH₂)_(s)—O—, wherein s is 1 to 3, preferably s is 2 yielding a1,3-dioxyethylene moiety.

Suitably, when X is the group OR₂, then R₂ is preferably an optionallysubstituted C₁₋₁₀ alkyl, an optionally substituted aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocyclic or heterocyclicalkyl moiety.Preferably, when the R₂ moiety is an alkyl it is a substituted orunsubstituted C₁₋₆ alkyl moiety as defined above. Preferably, the alkylsubstituents are independently selected from halogen, (CR₁₀R₂₀)_(n)OR₆,or (CR₁₀R₂₀)_(n)NR₄R₁₄.

When R₂ is an optionally substituted heterocyclic or heterocyclic alkylring, it is preferably a pyrrolidine, piperidine, piperazine, ormorpholine ring, or a pyrrolidinyl alkyl, piperidinyl alkyl, piperazinylalkyl, or a morpholinyl alkyl ring. More preferably, it is a piperidineor an alkyl substituted piperidine, such as N-methyl piperidine.

Preferred substituents include halogen, C₁₋₁₀alkyl, halosubstitutedC₁₋₁₀alkyl, (CR₁₀R₂₀)_(n)NR₄R₁₄, (CR₁₀R₂₀)_(n)OR₆, and(CR₁₀R₂₀)_(n)C(Z)OR₆.

Preferably, when X is the group S(O)_(m)R₂, R₂ is a substituted orunsubstituted C₁₋₁₀alkyl, aryl or arylalkyl.

Preferably, when X is the group (CH₂)_(n)NR₄R₁₄, n is preferably 0 or 1,more preferably 0. Preferably if the R₄ and R₁₄ moiety cyclize the ringis a 5 or 6 membered ring, such as a pyrrolidine, piperidine,piperazine, or morpholine containing ring, which ring may be optionallysubstituted. Preferably, when R₄ or R₁₄ is an optionally substitutedC₁₋₆alkyl, which chain may be a straight or branched chain, it issubstituted one or more times, suitably 1 to 4 times, preferably 1 or 2times, with halogen; hydroxy; hydroxy substituted C₁₋₁₀alkyl; C₁₋₁₀alkoxy; halosubstituted C₁₋₁₀ alkoxy; S(O) m C₁₋₄alkyl, wherein m is 0,1 or 2; NR₄R₁₄, such as amino or mono or -disubstituted C₁₋₆ alkyl orwherein the R₄R₁₄ can cyclize together with the nitrogen to which theyare attached to form a 5 to 7 membered ring which optionally contains anadditional heteroatom selected from O/N/S; C₃₋₇cycloalkyl;C₃₋₇cycloalkyl C₁₋₁₀ alkyl group; halosubstituted C₁₋₁₀ alkyl, suchCF₂CF₂H, or CF₃; optionally substituted aryl, such as phenyl, or anoptionally substituted arylalkyl, such as benzyl or phenethyl; andwherein these aryl or arylalkyl moieties may also themselves besubstituted one to two times by halogen; hydroxy; hydroxy substitutedalkyl; C₁₋₁₀ alkoxy; S(O)_(m) C₁₋₄ alkyl; amino, mono & di-substitutedC₁₋₆ alkyl amino, such as in the NR₄R₁₄ group; C₁₋₄ alkyl, or CF₃.

Preferably, the alkyl chain is branched, such as in t-butyl orisopropyl. More preferably the alkyl chain is substituted one or moretimes, independently by halogen, hydroxy, amino, or mono or di C₁₋₄alkyl substituted amino.

Preferably, when X is the group (CH₂)_(n)NR₂R₄, n is preferably 0 or 1,more preferably 0. The R₂ moiety is preferably, hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted heterocyclic,substituted or unsubstituted heterocyclic alkyl, substituted orunsubstituted heteroaryl, or substituted or unsubstitutedheteroarylalkyl. Such groups preferably include imidazole, tetrazole,pyrrolidine, piperidine, piperazine, morpholine, and 2-, 3- or4-pyridyl, pyrrolidinyl alkyl, piperidinyl alkyl, piperazinyl alkyl, ormorpholinyl alkyl.

Preferably, when X is the group R₂, then R₂ is preferably an optionallysubstituted heteroaryl, such as an imidazole, or tetrazole, or is anoptionally substituted heterocyclic ring, such as a pyrrolidine,piperidine, piperazine, or a morpholine ring

Another aspect of the present invention are the novel compounds ofFormula (III) and (IIIa).

Suitably, for compounds of Formula (III) and (IIa), R₁ is an aryl orheteroaryl ring, which ring may be optionally substituted. The ring maybe substituted one or more times, in any ring, suitably 1 to 4 times,preferably 1 to times, independently, by halogen, C₁₋₄ alkyl,halo-substituted-C₁₋₄ alkyl, cyano, nitro, (CR₁₀R₂₀)_(v)NR₄R₁₄,(CR₁₀R₂₀)_(v)C(Z)NR₄R₁₄, (CR₁₀R₂₀)_(v)C(Z)OR₈, (CR₁₀R₂₀)_(v)COR_(a),(CR₁₀R₂₀)_(v)C(O)H, S(O)_(m)R₅, (CR₁₀R₂₀)_(v)OR₈, ZC(Z)R₁₁, NR₁₀C(Z)R₁₁,or NR₁₀S(O)₂R₇. Preferably the ring is an aryl ring, more preferablyphenyl, which ring is unsubstituted or substituted one or more times byhalogen, preferably chloro or fluoro, or alkyl, preferably methyl.Suitably, the ring is substituted in the 4-position, and ifdi-substituted, it is in the 2-, 4-position of the phenyl ring.

Suitably m is 0 or an integer having a value of 1 or 2.

Suitably, v is 0 or an integer having a value of 1 or 2.

Suitably, Z is oxygen or sulfur.

Suitably, R_(a) is C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, C₃₋₇ cycloalkyl, C₅₋₇ cycloalkenyl, aryl,arylC₁₋₄ alkyl, heteroaryl, heteroarylC₁₋₄ alkyl, heterocyclyl,heterocyclylC₁₋₄ alkyl, (CR₁₀R₂₀)_(v)OR₇, (CR₁₀R₂₀)_(v)S(O)_(m)R₇,(CR₁₀R₂₀)_(v)NHS(O)₂R₇, or (CR₁₀R₂₀)_(v)NR₄R₁₄; and wherein the alkyl,cycloalkyl, cycloalkenyl, aryl, arylalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, and heteroarylalkyl moieties may beoptionally substituted.

Suitably, R₄ and R₁₄ are each independently selected from hydrogen,optionally substituted C₁₋₆ alkyl, optionally substituted aryl, or anoptionally substituted aryl-C₁₋₆ alkyl; or R₄ and R₁₄ together with thenitrogen which they are attached form a heterocyclic ring of 5 to 7members which ring optionally contains an additional heteroatom selectedfrom oxygen, sulfur or NR₉, and which ring may be optionallysubstituted.

Suitably, R₅ is hydrogen, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl orNR₄R₁₄, excluding the moieties SR₅ (wherein m is 0) being SNR₄R₁₄,S(O)₂R₅ being SO₂H (wherein m is 2) and S(O)R₅ being SOH, (wherein m is1).

Suitably, R₆ is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, heterocyclyl,heterocyclyl C₁₋₁₀alkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl or aheteroarylC₁₋₁₀ alkyl moiety; and wherein each of these moieties,excluding hydrogen, may be optionally substituted.

Suitably, R₇ is C₁₋₆alkyl, aryl, arylC₁₋₆alkyl, heterocyclic,heterocyclylC₁₋₆ alkyl, heteroaryl, or heteroarylC₁₋₆alkyl moiety; andwherein each of these moieties may be optionally substituted.

Suitably, R₈ is hydrogen, C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, C₃₋₇ cycloalkyl, C₅₋₇ cycloalkenyl, aryl, arylC₁₋₄alkyl, heteroaryl, heteroarylC₁₋₄ alkyl, heterocyclyl,heterocyclylC₁₋₄ alkyl, (CR₁₀R₂₀)_(t)OR₇, (CR₁₀R₂₀)_(t)S(O)_(m)R₇,(CR₁₀R₂₀)_(t)NHS(O)₂R₇, or (CR₁₀R₂₀)_(t)NR₄R₁₄; and wherein the alkyl,cycloalkyl, cycloalkenyl, aryl, arylalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, and heteroaryl alkyl moieties, may beoptionally substituted.

Suitably, t is an integer having a value of 1 to 3.

Suitably, R₉ is hydrogen, C(Z)R₆, optionally substituted C₁₋₁₀ alkyl,optionally substituted aryl or optionally substituted aryl-C₁₋₄ alkyl.

Suitably, R₁₀ and R₂₀ are each independently selected from hydrogen orC₁₋₄ alkyl.

Suitably, R₁₁ is C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, C₂₋₄ alkenyl,C₂₋₄ alkynyl, C₃₋₇ cycloalkyl, C₅₋₇ cycloalkenyl, aryl, arylC₁₋₄ alkyl,heteroaryl, heteroarylC₁₋₄ alkyl, heterocyclyl, heterocyclylC₁₋₄ alkyl,(CR₁₀R₂₀)_(t)OR₇, (CR₁₀R₂₀)_(t)S(O)_(m)R₇, (CR₁₀R₂₀)_(t)NHS(O)₂R₇, or(CR₁₀R₂₀)_(v)NR₄R₁₄; and wherein the alkyl, cycloalkyl, cycloalkenyl,aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, andheteroaryl alkyl moieties may be optionally substituted.

Suitably X is R_(2′), OR₂, S(O)_(m)R₂ or (CH₂)_(n)NR₄R₁₄, or(CH₂)_(n)NR₂R₄; provided that when is X is (CH₂)_(n)NR₄R₁₄, then R₄R₁₄forms the optionally substituted cyclized ring optionally comprising anoxygen, sulfur or nitrogen moiety as defined herein.

Suitably, R₃ is an optionally substituted aryl, or optionallysubstituted heteroaryl moiety. The R₃ moieties be optionally substitutedone or more times independently with C₁₋₁₀ alkyl, halo-substituted C₁₋₁₀alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₇ cycloalkyl,C₃₋₇cycloalkylC₁₋₁₀ alkyl, C₅₋₇ cycloalkenyl, C₅₋₇ cycloalkenyl C₁₋₁₀alkyl, halogen, (CR₁₀R₂₀)_(n)OR₆, (CR₁₀R₂₀)_(n)SH,(CR₁₀R₂₀)_(n)S(O)_(m)R₇, (CR₁₀R₂₀)_(n)NHS(O)₂R₇, (CR₁₀R₂₀)_(n)NR₄R₁₄,(CR₁₀R₂₀)_(n)CN, (CR₁₀R₂₀)_(n)S(O)₂NR₄R₄, (CR₁₀R₂₀)_(n)C(Z)R₆,(CR₁₀R₂₀)_(n)OC(Z)R₆, (CR₁₀R₂₀)_(n)C(Z)OR₆, (CR₁₀R₂₀)_(n)C(Z)NR₄R₁₄,(CR₁₀R₂₀)_(n)NR₁₀C(Z)R₆, (CR₁₀R₂₀)_(n)NR₁₀C(═NR₁₀)NR₄R₁₄,(CR₁₀R₂₀)_(n)OC(Z)NR₄R₁₄, (CR₁₀R₂₀)_(n)NR₁₀C(Z)NR₄R₁₄, or(CR₁₀R₂₀)_(n)NR₁₀C(Z)OR₇.

Preferably, R₃ is an optionally substituted aryl, more preferablyoptionally substituted phenyl. Preferably, the ring is unsubstituted orsubstituted one or more times, independently with halogen, morepreferably fluorine, or chlorine, or alkyl, such as methyl. The ring ispreferably substituted in the 2-position or di-substituted in the 2-,6-position, more preferably with fluorine, methyl, difluoro, ordimethyl.

Suitably, n is 0, or an integer having a value of 1 to 10. Suitably, R₂is a heterocyclic, or heterocyclylC₁₋₁₀ alkyl ring, which ring orrings(s) are optionally substituted one or more times, suitably 1 to 4,independently with C₁ ₋₁₀ alkyl, halo-substituted C₁₋₁₀ alkyl, C₂₋₁₀alkenyl, C₂₋₁₀ alkynyl, C₃₋₇ cycloalkyl, C₃₋₇cycloalkylC₁₋₁₀ alkyl, C₅₋₇cycloalkenyl, C₅₋₇ cycloalkenyl C₁₋₁₀ alkyl, halogen, (CR₁₀R₂₀)_(n)OR₆,(CR₁₀R₂₀)_(n)SH, (CR₁₀R₂₀)_(n)S(O)_(m)R₇, (CR₁₀R₂₀)_(n)NHS(O)₂R₇,(CR₁₀R₂₀)_(n)NR₄R₁₄, (CR₁₀R₂₀)_(n)CN, (CR₁₀R₂₀)_(n)S(O)₂NR₄R₁₄,(CR₁₀R₂₀)_(n)C(Z)R₆, (CR₁₀R₂₀)_(n)OC(Z)R₆, (CR₁₀R₂₀)_(n)C(Z)OR₆,(CR₁₀R₂₀)_(n)C(Z)NR₄R₁₄, (CR₁₀R₂₀)_(n)NR₁₀C(Z)R₆,(CR₁₀R₂₀)_(n)NR₁₀C(═NR₁₀)NR₄R₁₄, (CR₁₀R₂₀)_(n)OC(Z)NR₄R₁₄,(CR₁₀R₂₀)_(n)NR₁₀C(Z)NR₄R₁₄, (CR₁₀R₂₀)_(n)NR₁₀C(Z)OR₇, or adioxyalkylene group of the formula —O—(CH₂)_(s)—O—, wherein s is 1 to 3,preferably s is 2 yielding a 1,3-dioxyethylene moiety. Suitably, R_(2′)is a heterocyclic, heterocyclylC₁₋₁₀ alkyl, aryl, or heteroaryl ring,which ring or rings(s) are optionally substituted one or more times,suitably 1 to 4 times, in any ring, independently with C₁₋₁₀ alkyl,halo-substituted C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₁₀ alkyl, C₅₋₇ cycloalkenyl, C₅₋₇cycloalkenyl C₁₋₁₀ alkyl, halogen, (CR₁₀R₂₀)_(n)OR₆, (CR₁₀R₂₀)_(n)SH,(CR₁₀R₂₀)_(n)S(O)_(m)R₇, (CR₁₀R₂₀)_(n)NHS(O)₂R₇, (CR₁₀R₂₀)_(n)NR₄R₁₄,(CR₁₀R₂₀)_(n)CN, (CR₁₀R₂₀)_(n)S(O)₂NR₄R₁₄, (CR₁₀R₂₀)_(n)C(Z)R₆,(CR₁₀R₂₀)_(n)OC(Z)R₆, (CR₁₀R₂₀)_(n)C(Z)OR₆, (CR₁₀R₂₀)_(n)C(Z)NR₄R₁₄,(CR₁₀R₂₀)_(n)NR₁₀C(Z)R₆, (CR₁₀R₂₀)_(n)NR₁₀C(═NR₁₀)NR₄R₁₄,(CR₁₀R₂₀)_(n)OC(Z)NR₄R₁₄, (CR₁₀R₂₀)_(n)NR₁₀C(Z)NR₄R₁₄,(CR₁₀R₂₀)_(n)NR₁₀C(Z)OR₇, or a dioxyalkylene group of the formula—O—(CH₂)_(s)—O—, wherein s is 1 to 3, preferably s is 2 yielding a1,3-dioxyethylene moiety.

Suitably, the optionally substituted R₂ or R_(2′) heterocyclic ring is apyrrolidine, piperidine, piperazine, or morpholine ring or apyrrolidinyl alkyl, piperidinyl alkyl, piperazinyl alkyl, or amorpholinyl alkyl. More preferably, it is a piperidine or an alkylsubstituted piperidine, such as N-methyl piperidine.

Suitably, when R_(2′) is an optionally substituted aryl or heteroarylring, the ring is an optionally substituted phenyl, imidazole ortetrazole ring.

Another aspect of the present invention is the novel compounds ofFormula (IV) and (IVa).

Suitably, for compounds of Formula (IV) and (IVa), R₁ is an aryl orheteroaryl ring, which ring is optionally substituted. The ring may besubstituted one or more times, in any ring, suitably 1 to 4 times,preferably 1 to 2 times, independently, by halogen, C₁₋₄ alkyl,halo-substituted-C₁₋₄ alkyl, cyano, nitro, (CR₁₀R₂₀)_(v)NR₄R₁₄,(CR₁₀R₂₀)_(v)C(Z)NR₄R₁₄, (CR₁₀R₂₀)_(v)C(Z)OR₈, (CR₁₀R₂₀)_(v)COR_(a),(CR₁₀R₂₀)_(v)C(O)H, S(O)_(m)R₅, (CR₁₀R₂₀)_(v)OR₈, ZC(Z)R₁, NR₁₀C(Z)R₁₁,or NR₁₀S(O)₂R₇. Preferably the ring is an aryl ring, more preferablyphenyl, which ring is unsubstituted or substituted one or more times byhalogen, preferably chloro or fluoro, or alkyl, preferably methyl.Suitably, the ring is substituted in the 4-position, and ifdi-substituted, it is in the 2-, 4-position of the phenyl ring. Mostpreferably R₁ is a 2-methyl-4-fluoro phenyl.

Suitably m is 0 or an integer having a value of 1 or 2.

Suitably, v is 0 or an integer having a value of 1 or 2.

Suitably, Z is oxygen or sulfur.

Suitably, R_(a) is C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, C₃₋₇ cycloalkyl, C₅₋₇ cycloalkenyl, aryl,arylC₁₋₄ alkyl, heteroaryl, heteroarylC₁₋₄ alkyl, heterocyclyl,heterocyclylC₁₋₄ alkyl, (CR₁₀R₂₀)_(v)OR₇, (CR₁₀R₂₀)_(v)S(O)_(m)R₇,(CR₁₀R₂₀)_(v)NHS(O)₂R₇, or (CR₁₀R₂₀)_(v)NR₄R₁₄; and wherein the alkyl,cycloalkyl, cycloalkenyl, aryl, arylalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, and heteroarylalkyl moieties may beoptionally substituted.

Suitably, R₄ and R₁₄ are each independently selected from hydrogen,optionally substituted C₁₋₆ alkyl, optionally substituted aryl or anoptionally substituted aryl-C₁₋₆ alkyl, or R₄ and R₁₄ together with thenitrogen which they are attached form a heterocyclic ring of 5 to 7members which ring optionally contains an additional heteroatom selectedfrom oxygen, sulfur or NR₉, and which ring may be optionallysubstituted.

Suitably, R₅ is hydrogen, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl orNR₄R₁₄, excluding the moieties SR₅ (wherein m is 0) being SNR₄R₁₄,S(O)₂R₅ being SO₂H (wherein m is 2) and S(O)R₅ being SOH, (wherein m is1).

Suitably, R₆ is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, heterocyclyl,heterocyclyl C₁₋₁₀alkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl orheteroarylC₁₋₁₀ alkyl; and wherein each of these moieties, excludinghydrogen, may be optionally substituted.

Suitably, R₇ is C₁₋₆alkyl, aryl, arylC₁₋₆alkyl, heterocyclic,heterocyclylC₁₋₆ alkyl, heteroaryl, or heteroarylC₁₋₆alkyl; and whereineach of these moieties may be optionally substituted.

Suitably, R₈ is hydrogen, C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, C₃₋₇ cycloalkyl, C₅₋₇ cycloalkenyl, aryl, arylC₁₋₄ alkyl, heteroaryl, heteroarylC₁₋₄ alkyl, heterocyclyl,heterocyclylC₁₋₄ alkyl, (CR₁₀R₂₀)_(t)OR₇, (CR₁₀R₂₀)_(t)S(O)_(m)R₇,(CR₁₀R₂₀)_(t)NHS(O)₂R₇, or (CR₁₀R₂₀)_(t)NR₄R₁₄; and wherein the alkyl,cycloalkyl, cycloalkenyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroaryl alkyl moieties may be optionallysubstituted.

Suitably, t is an integer having a value of 1 to 3.

Suitably, R₉ is hydrogen, C(Z)R₆, optionally substituted C₁₋₁₀ alkyl,optionally substituted aryl or optionally substituted aryl-C₁₋₄ alkyl.

Suitably, R₁₀ and R₂₀ are each independently selected from hydrogen orC₁₋₄ alkyl.

Suitably, R₁₁ is C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, C₂₋₄ alkenyl,C₂₋₄ alkynyl, C₃₋₇ cycloalkyl, C₅₋₇ cycloalkenyl, aryl, arylC₁₋₄ alkyl,heteroaryl, heteroarylC₁₋₄ alkyl, heterocyclyl, heterocyclylC₁₋₄ alkyl,(CR₁₀R₂₀)_(t)OR₇, (CR₁₀R₂₀)_(t)S(O)_(m)R₇, (CR₁₀R₂₀)_(t)NHS(O)₂R₇, or(CR₁₀R₂₀)_(v)NR₄R₁₄; and wherein the alkyl, cycloalkyl, cycloalkenyl,aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, andheteroaryl alkyl moieties may be optionally substituted.

Suitably, R₃ is hydrogen, an C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl,C₃₋₇cycloalkylC₁₋₁₀alkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl,heteroarylC₁₋₁₀ alkyl, heterocyclic, or a heterocyclylC₁₋₁₀ alkylmoiety; and wherein each of these moieties, excluding hydrogen, may beoptionally substituted, independently, one or more times, suitably 1 to4 times, preferably 1 to 2 times, in any ring if applicable, with C₁₋₁₀alkyl, halo-substituted C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₁₀ alkyl, C₅₋₇ cycloalkenyl, C₅₋₇cycloalkenyl C₁₋₁₀ alkyl, halogen, (CR₁₀R₂₀)_(n)OR₆, (CR₁₀R₂₀)_(n)SH,(CR₁₀R₂₀)_(n)S(O)_(m)R₇, (CR₁₀R₂₀)_(n)NHS(O)₂R₇, (CR₁₀R₂₀)_(n)NR₄R₁₄(CR₁₀R₂₀)_(n)CN, (CR₁₀R₂₀)_(n) S(O)₂NR₄R₁₄, (CR₁₀R₂₀)_(n)C(Z)R₆,(CR₁₀R₂₀)_(n)OC(Z)R₆, (CR₁₀R₂₀)_(n)C(Z)OR₆, (CR₁₀R₂₀)_(n)C(Z)NR₄R₁₄,(CR₁₀R₂₀)_(n)NR₁₀C(Z)R₆, (CR₁₀R₂₀)_(n)NR₁₀C(═NR₁₀)NR₄R₁₄,(CR₁₀R₂₀)_(n)OC(Z)NR₄R₁₄, (CR₁₀R₂₀)_(n)NR₁₀C(Z)NR₄R₁₄, or(CR₁₀R₂₀)_(n)NR₁₀C(Z)OR₇.

Preferably, R₃ is an optionally substituted C₁₋₁₀alkyl, aryl, arylC₁₋₅alkyl, or a cycloalkyl moiety, more preferably optionally substitutedC₁₋₅ alkyl, cyclohexyl, phenyl, benzyl or phenethyl. Preferably, thering is unsubstituted or substituted one or more times, independentlywith halogen, more preferably fluorine, or chlorine, or alkyl, such asmethyl. The ring is preferably substituted in the 2-position ordi-substituted in the 2-, 6-position, more preferably with fluorine,methyl, difluoro, or dimethyl.

Suitably, X is R₂, OR₂, S(O)_(m)R₂, (CH₂)_(n)NR₄R₁₄, or (CH₂)_(n)NR₂R₄.

Suitably, R₂ is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇cycloalkylC₁₋₁₀alkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl, heteroarylC₁₋₁₀alkyl, heterocyclic, or a heterocyclylC₁₋₁₀ alkyl moiety; and whereineach of these moieties, excluding hydrogen, may optionally substitutedone or more times, suitable 1 to 4 times, independently, and in anyring, with C₁₋₁₀ alkyl, halo-substituted C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl,C₂₋₁₀ alkynyl, C₃₋₇ cycloalkyl, C₃₋₇cycloalkylC₁₋₁₀ alkyl, C₅₋₇cycloalkenyl, C₅₋₇ cycloalkenyl C₁₋₁₀ alkyl, halogen, (CR₁₀R₂₀)_(n)OR₆,(CR₁₀R₂₀)_(n)SH, (CR₁₀R₂₀)_(n)S(O)_(m)R₇, (CR₁₀R₂₀)_(n)NHS(O)₂R₇,(CR₁₀R₂₀)_(n)NR₄R₁₄, (CR₁₀R₂₀)_(n)CN, (CR₁₀R₂₀)_(n)S(O)₂NR₄R₁₄,(CR₁₀R₂₀)_(n)C(Z)R₆, (CR₁₀R₂₀)_(n)OC(Z)R₆, (CR₁₀R₂₀)_(n)C(Z)OR₆,(CR₁₀R₂₀)_(n)C(Z)NR₄R₁₄, (CR₁₀R₂₀)_(n)NR₁₀C(Z)R₆,(CR₁₀R₂₀)_(n)NR₁₀C(═NR₁₀)NR₄R₁₄, (CR₁₀R₂₀)_(n)OC(Z)NR₄R₁₄,(CR₁₀R₂₀)_(n)NR₁₀C(Z)NR₄R₁₄, (CR₁₀R₂₀)_(n)NR₁₀C(Z)OR₇, or adioxyalkylene group of the formula —O—(CH₂)_(s)—O—, wherein s is 1 to 3,preferably s is 2 yielding a 1,3-dioxyethylene moiety.

Suitably, n is 0, or an integer having a value of 1 to 10.

Suitably, when X is the group OR₂, then R₂ is preferably an optionallysubstituted C₁₋₁₀ alkyl, an optionally substituted aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocyclic or heterocyclicalkyl moiety.Preferably, when the R₂ moiety is an alkyl it is a substituted orunsubstituted C₁₋₆ alkyl. Suitably, the alkyl substituents are halogen,(CR₁₀R₂₀)_(n)OR₆, (CR₁₀R₂₀)_(n)SH, (CR₁₀R₂₀)_(n)S(O)_(m)R₇,(CR₁₀R₂₀)_(n)NHS(O)₂R₇, (CR₁₀R₂₀)_(n)N₄R₁₄, (CR₁₀R₂₀)_(n)CN,(CR₁₀R₂₀)_(n) S(O)₂NR₄R₁₄, (CR₁₀R₂₀)_(n)C(Z)R₆, (CR₁₀R₂₀)_(n)OC(Z)R₆,(CR₁₀R₂₀)_(n)C(Z)OR₆, (CR₁₀R₂₀)_(n)C(Z)NR₄R₁₄, (CR₁₀R₂₀)_(n)NR₁₀C(Z)R₆,(CR₁₀R₂₀)_(n)NR₁₀C(═NR₁₀)NR₄R₁₄, (CR₁₀R₂₀)_(n)OC(Z)NR₄R₁₄,(CR₁₀R₂₀)_(n)NR₁₀C(Z)NR₄R₁₄, or (CR₁₀R₂₀)_(n)NR₁₀C(Z)OR₇.

Preferably, the alkyl substituents are halogen, (CR₁₀R₂₀)_(n)OR₆, or(CR₁₀R₂₀)_(n)NR₄R₁₄.

When R₂ is an optionally substituted heterocyclic or heterocyclic alkylring, it is preferably a pyrrolidine, piperidine, piperazine, ormorpholine ring, or is a pyrrolidinyl alkyl, piperidinyl alkyl,piperazinyl alkyl, or morpholinyl alkyl ring. More preferably, it is apiperidine or an alkyl substituted piperidine, such as N-methylpiperidine.

Preferred substituents include halogen, C₁₋₁₀alkyl, halosubstitutedC₁₋₁₀alkyl, (CR₁₀R₂₀)_(n)NR₄R₁₄, (CR₁₀R₂₀)_(n)OR₆, and(CR₁₀R₂₀)_(n)C(Z)OR₆.

Preferably when X is the group S(O)_(m)R₂, R₂ is a substituted orunsubstituted C₁₋₁₀alkyl, aryl or arylalkyl. While the X groupS(O)_(m)R₂ moiety is a compound of Formula (IV) it is also a keyintermediate in the process of making other compounds of Formula (IV) ascan be seen by Scheme I herein. Preferably for this use, m is 0 and R₂is a short chain alkyl, such as methyl.

Preferably, when X is the group (CH₂)_(n)NR₄R₁₄, n is preferably 0 or 1,more preferably 0. Preferably, if the R₄ and R₁₄ moiety cyclize the ringis a 5 or 6 membered ring, such as a pyrrolidine, piperidine,piperazine, or morpholine containing ring, which ring may be optionallysubstituted. Preferably, when R₄ or R₁₄ is an optionally substitutedC₁₋₆alkyl, which chain may be a straight or branched chain, it issubstituted one or more times, independently, suitably 1 to 4 times,preferably 1 or 2 times, with halogen; hydroxy; hydroxy substituted C₁₋₁₀alkyl; C₁₋₁₀ alkoxy; halosubstituted C₁₋₁₀ alkoxy; S(O)m C₁₋₄alkyl,wherein m is 0, 1 or 2; NR₄R₁₄, such as amino or mono or -disubstitutedC₁₋₄ alkyl or wherein the R₄R₁₄ can cyclize together with the nitrogento which they are attached to form a 5 to 7 membered ring whichoptionally contains an additional heteroatom selected from O/N/S;C₃₋₇cycloalkyl; C₃₋₇cycloalkyl C₁₋₁₀ alkyl group; halosubstituted C₁₋₁₀alkyl, such CF₂CF₂H, or CF₃; optionally substituted aryl, such asphenyl, or an optionally substituted arylalkyl, such as benzyl orphenethyl; and wherein these aryl or arylalkyl moieties may alsothemselves be substituted one to two times by halogen; hydroxy; hydroxysubstituted alkyl; C₁₋₁₀ alkoxy; S(O)_(m)C₁₋₄ alkyl; amino, mono &di-substituted C₁₋₄ alkyl amino, such as in the NR₄R₁₄ group; C₁₋₄alkyl, or CF₃.

Preferably, the alkyl chain is branched, such as in t-butyl orisopropyl. More preferably the alkyl chain is substituted one or moretimes, independently by halogen, hydroxy, amino, or mono or di C₁₋₄alkyl substituted amino.

Preferably, when X is the group (CH₂)_(n)NR₂R₄, n is preferably 0 or 1,more preferably 0. Preferably one of R₂ or R₄ is hydrogen and the otheris an optionally substituted moiety. The R₂ moiety is preferably,hydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted heterocyclic, substituted or unsubstituted heterocyclicalkyl, substituted or unsubstituted heteroaryl, or substituted orunsubstituted heteroarylalkyl. When R₂ is an optionally substitutedheterocyclic, heterocyclic alkyl, or heteroaryl group such groups arepreferably an imidazole, tetrazole, pyrrolidine, piperidine, piperazine,morpholine and 2-, 3- or 4-pyridyl; pyrrolidinyl alkyl, piperidinylalkyl, piperazinyl alkyl, or morpholinyl alkyl.

When the R₂ moiety is an optionally substituted C₁₋₁₀ alkyl, the chainmay be straight or branched, and substituted one or more times, suitably1 to 4 times, independently by halogen, (CR₁₀R₂₀)_(n)OR₆,(CR₁₀R₂₀)_(n)SH, (CR₁₀R₂₀)_(n)S(O)_(m)R₇, (CR₁₀R₂₀)_(n)NHS(O)₂R₇,(CR₁₀R₂₀)_(n)N₄R₁₄, (CR₁₀R₂₀)_(n)CN, (CR₁₀R₂₀)_(n)S(O)₂NR₄R₁₄,(CR₁₀R₂₀)_(n)C(Z)R₆, (CR₁₀R₂₀)_(n)OC(Z)R₆, (CR₁₀R₂₀)_(n)C(Z)OR₆,(CR₁₀R₂₀)_(n)C(Z)NR₄R₁₄, (CR₁₀R₂₀)_(n)NR₁₀C(Z)R₆,(CR₁₀R₂₀)_(n)NR₁₀C(═NR₁₀)NR₄R₁₄, (CR₁₀R₂₀)_(n)OC(Z)NR₄R₁₄,(CR₁₀R₂₀)_(n)NR₁₀C(Z)NR₄R₁₄, (CR₁₀R₂₀)_(n)NR₁₀C(Z)OR₇, or dioxyalkylenegroup of the formula —O—(CH₂)_(s)—O—, wherein s is 1 to 3, preferably sis 2 yielding a 1,3-dioxyethylene moiety.

Preferably, when X is the group R₂, then R₂ is preferably an optionallysubstituted heteroaryl, such as an imidazole, or tetrazole, or is anoptionally substituted heterocyclic ring, such as a pyrrolidine,piperidine, piperazine, or morpholine ring.

Suitably, Y is a bond, CR_(b), C(O), N(R_(d)), oxygen, or S(O)_(m).Preferably Y is a bond.

Suitably, R_(b) is hydrogen, C₁₋₂ alkyl, NR_(C), hydroxy, thio, C₁₋₂alkoxy, S(O)_(m)C₁₋₁₂ alkyl.

Suitably, R_(c) is hydrogen or C₁₋₂ alkyl.

Suitably, R_(d) is hydrogen or C₁₋₂ alkyl.

Suitably, m is 0 or an integer having a value of 1 or 2.

Another aspect of the present invention is the novel compounds ofFormula (V) and (Va).

Suitably, for compounds of Formula (V) and (Va), R₁ is an optionallysubstituted aryl ring, preferably a phenyl ring. The phenyl or napthylring or ring(s) may be substituted one or more times, in any ring,preferably 1 to 4 times, independently, by substituents selected fromhalogen, C₁₋₄ alkyl, halo-substituted-C₁₋₄ alkyl, cyano, nitro,(CR₁₀R₂₀)_(v)NR₄R₁₄, (CR₁₀R₂₀)_(v)C(Z)NR₄R₁₄, (CR₁₀R₂₀)_(v)C(Z)OR₈,(CR₁₀R₂₀)_(v)COR_(a), (CR₁₀R₂₀)_(v)C(O)H, S(O)_(m)R₅, (CR₁₀R₂₀)_(v)OR₈,ZC(Z)R₁₁, NR₁₀C(Z)R₁₁, or NR₁₀S(O)₂R₇. Preferably the ring isunsubstituted or substituted one or more times by halogen, preferablychloro or fluoro, or alkyl, preferably methyl. Suitably, the ring issubstituted in the 4-position, and if di-substituted, in the 2-,4-position of the phenyl ring.

Suitably, v is 0 or an integer having a value of 1 or 2.

Suitably, Z is oxygen or sulfur.

Suitably, R_(a) is C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, C₃₋₇ cycloalkyl, C₅₋₇ cycloalkenyl, aryl,arylC₁₋₄ alkyl, heteroaryl, heteroarylC₁₋₄ alkyl, heterocyclyl,heterocyclylC₁₋₄ alkyl, (CR₁₀R₂₀)_(v)OR₇, (CR₁₀R₂₀)_(v)S(O)_(m)R₇,(CR₁₀R₂₀)_(v)NHS(O)₂R₇, or (CR₁₀R₂₀)_(v)NR₄R₁₄; and wherein the alkyl,cycloalkyl, cycloalkenyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroaryl alkyl moieties may be optionallysubstituted.

Suitably, R₄ and R₁₄ is each independently selected from hydrogen,optionally substituted C₁₋₆ alkyl, optionally substituted aryl oroptionally substituted aryl-C₁₋₆ alkyl, or together with the nitrogenwhich they are attached form a heterocyclic ring of 5 to 7 members whichring optionally contains an additional heteroatom selected from oxygen,sulfur or NR₉, which ring may be optionally substituted.

Suitably, R₅ is hydrogen, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl orNR₄R₁₄, excluding the moieties SR₅ (wherein m is 0) being SNR₄R₁₄,S(O)₂R₅ being SO₂H (wherein m is 2) and S(O)R₅ being SOH, (wherein m is1).

Suitably, R₆ is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, heterocyclyl,heterocyclyl C₁₋₁₀alkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl orheteroarylC₁₋₁₀ alkyl; and wherein each of these moieties, excludinghydrogen, may be optionally substituted.

Suitably, R₇ is C₁₋₆alkyl, aryl, arylC₁₋₆alkyl, heterocyclic,heterocyclylC₁₋₆ alkyl, heteroaryl, or heteroarylC₁₋₆alkyl; and whereineach of these moieties may be optionally substituted.

Suitably, R₈ is hydrogen, C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, C₃₋₇ cycloalkyl, C₅₋₇ cycloalkenyl, aryl, arylC₁₋₄ alkyl, heteroaryl, heteroarylC₁₋₄ alkyl, heterocyclyl,heterocyclylC₁₋₄ alkyl, (CR₁₀R₂₀)_(t)OR₇, (CR₁₀R₂₀)_(t)S(O)_(m)R₇,(CR₁₀R₂₀)_(t)NHS(O)₂R₇, or (CR₁₀R₂₀)_(t)NR₄R₁₄; and wherein the alkyl,cycloalkyl, cycloalkenyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroaryl alkyl moieties may be optionallysubstituted.

Suitably, t is an integer having a value of 1 to 3.

Suitably, R₉ is hydrogen, C(Z)R₆, optionally substituted C₁₋₁₀ alkyl,optionally substituted aryl or optionally substituted aryl-C₁₋₄ alkyl.

Suitably, R₁₀ and R₂₀ are each independently selected from hydrogen orC₁₋₄ alkyl.

Suitably, R₁₁ is C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, C₂₋₄ alkenyl,C₂₋₄ alkynyl, C₃₋₇ cycloalkyl, C₅₋₇ cycloalkenyl, aryl, arylC₁₋₄ alkyl,heteroaryl, heteroarylC₁₋₄ alkyl, heterocyclyl, heterocyclylC₁₋₄ alkyl,(CR₁₀R₂₀)_(t)OR₇, (CR₁₀R₂₀)_(t)S(O)_(m)R₇, (CR₁₀R₂₀)_(t)NHS(O)₂R₇, or(CR₁₀R₂₀)_(v)NR₄R₁₄; and wherein the alkyl, cycloalkyl, cycloalkenyl,aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, andheteroaryl alkyl moieties may be optionally substituted.

Suitably m is 0 or an integer having a value of 1 or 2. Suitably, R₂ ishydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇cycloalkylC₁₋₁₀alkyl, aryl,arylC₁₋₁₀ alkyl, heteroaryl, heteroarylC₁₋₁₀ alkyl, heterocyclic, or aheterocyclylC₁₀ alkyl moiety; and wherein each of these moieties,excluding hydrogen, may optionally substituted one or more timesindependently, preferably 1 to 2 times, with C₁₋₁₀ alkyl,halo-substituted C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₁₀ alkyl, C₅₋₇ cycloalkenyl, C₅₋₇cycloalkenyl C₁₋₁₀ alkyl, halogen, (CR₁₀R₂₀)_(n)OR₆, (CR₁₀R₂₀)_(n)SH,(CR₁₀R₂₀)_(n)S(O)_(m)R₇, (CR₁₀R₂₀)_(n)NHS(O)₂R₇, (CR₁₀R₂₀)_(n)NR₄R₁₄,(CR₁₀R₂₀)_(n)CN, (CR₁₀R₂₀)_(n)S(O)₂NR₄R₁₄, (CR₁₀R₂₀)_(n)C(Z)R₆,(CR₁₀R₂₀)_(n)OC(Z)R₆, (CR₁₀R₂₀)_(n)C(Z)OR₆, (CR₁₀R₂₀)_(n)C(Z)NR₄R₁₄,(CR₁₀R₂₀)_(n)NR₁₀C(Z)R₆, (CR₁₀R₂₀)_(n)NR₁₀C(═NR₁₀)NR₄R₁₄,(CR₁₀R₂₀)_(n)OC(Z)NR₄R₁₄, (CR₁₀R₂₀)_(n)NR₁₀C(Z)NR₄R₁₄,(CR₁₀R₂₀)_(n)NR₁₀C(Z)OR₇, or a dioxyalkylene group of the formula—O—(CH₂)_(s)—O—, wherein s is 1 to 3, preferably s is 2 yielding a1,3-dioxyethylene moiety.

Suitably, R₃ is an optionally substituted aryl ring, which ring may beoptionally substituted one or more times, independently, in any ring,with C₁₋₁₀ alkyl, halo-substituted C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, C₃₋₇ cycloalkyl, C₃₋₇cycloalkylC₁₋₁₀ alkyl, C₅₋₇ cycloalkenyl,C₅₋₇ cycloalkenyl C₁₋₁₀ alkyl, halogen, (CR₁₀R₂₀)_(n)OR₆,(CR₁₀R₂₀)_(n)SH, (CR₁₀R₂₀)_(n)S(O)_(m)R₇, (CR₁₀R₂₀)_(n)NHS(O)₂R₇,(CR₁₀R₂₀)_(n)NR₄R₁₄, (CR₁₀R₂₀)_(n)CN, (CR₁₀R₂₀)_(n)S(O)₂NR₄R₁₄,(CR₁₀R₂₀)_(n)C(Z)R₆, (CR₁₀R₂₀)_(n)OC(Z)R₆, (CR₁₀R₂₀)_(n)C(Z)OR₆,(CR₁₀R₂₀)_(n)C(Z)NR₄R₁₄, (CR₁₀R₂₀)_(n)NR₁₀C(Z)R₆,(CR₁₀R₂₀)_(n)NR₁₀C(═NR₁₀)NR₄R₁₄, (CR₁₀R₂₀)_(n)OC(Z)NR₄R₁₄,(CR₁₀R₂₀)_(n)NR₁₀C(Z)NR₄R₁₄, or (CR₁₀R₂₀)_(n)NR₁₀C(Z)OR₇.

Preferably, R₃ is an optionally substituted phenyl. Preferably, the ringis unsubstituted or substituted one or more times, independently withhalogen, more preferably fluorine, or chlorine, or alkyl, such asmethyl. The ring is preferably substituted in the 2-position ordi-substituted in the 2-, 6-position, more preferably with fluorine,methyl, difluoro, or dimethyl.

Suitably, n is 0, or an integer having a value of 1 to 10.

Suitably, X is R₂, OR₂, S(O)_(m)R₂, (CH₂)_(n)NR₄R₁₄, or (CH₂)_(n)NR₂R₄.

Suitably, when X is the group OR₂, then R₂ is preferably an optionallysubstituted C₁₋₁₀ alkyl, an optionally substituted aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocyclic or heterocyclicalkyl moiety.Preferably, when the R₂ moiety is an alkyl it is a substituted orunsubstituted C₁₋₆ alkyl moiety. Preferably, the alkyl substituents areindependently selected from halogen, (CR₁₀R₂₀)_(n)OR₆, or(CR₁₀R₂₀)_(n)NR₄R₁₄.

When R₂ is an optionally substituted heterocyclic or heterocyclic alkylring, it is preferably a pyrrolidine, piperidine, piperazine, ormorpholine ring, or a pyrrolidinyl alkyl, piperidinyl alkyl, piperazinylalkyl, or a morpholinyl alkyl ring. More preferably, it is a piperidineor an alkyl substituted piperidine, such as N-methyl piperidine.

Preferred substituents include halogen, C₁₋₁₀alkyl, halosubstitutedC₁₋₁₀alkyl, (CR₁₀R₂₀)_(n)NR₄R₁₄, (CR₁₀R₂₀)_(n)OR₆, and(CR₁₀R₂₀)_(n)C(Z)OR₆.

Preferably when X is the group S(O)_(m)R₂, and R₂ is a substituted orunsubstituted C₁₋₁₀alkyl, aryl or arylalkyl.

Preferably, when X is the group (CH₂)_(n)NR₄R₁₄, n is preferably 0 or 1,more preferably 0. Preferably if the R₄ and R₁₄ moiety cyclize the ringis a 5 or 6 membered ring, such as a pyrrolidine, piperidine,piperazine, or morpholine containing ring, which ring may be optionallysubstituted. Preferably, when R₄ or R₁₄ is an optionally substitutedC₁₋₆alkyl, which chain may be a straight or branched chain, it issubstituted one or more times, suitably 1 to 4 times, preferably 1 or 2times, with halogen; hydroxy; hydroxy substituted C₁₋₁₀alkyl; C₁₋₁₀alkoxy; halosubstituted C₁₋₁₀ alkoxy; S(O)m C₁₋₄alkyl, wherein m is 0, 1or 2; NR₄R₁₄, such as amino or mono or -disubstituted C₁₋₆ alkyl orwherein the R₄R₁₄ can cyclize together with the nitrogen to which theyare attached to form a 5 to 7 membered ring which optionally contains anadditional heteroatom selected from O/N/S; C₃₋₇cycloalkyl;C₃₋₇cycloalkyl C₁₋₁₀ alkyl group; halosubstituted C₁₋₁₀ alkyl, suchCF₂CF₂H, or CF₃; optionally substituted aryl, such as phenyl, or anoptionally substituted arylalkyl, such as benzyl or phenethyl; andwherein these aryl or arylalkyl moieties may also themselves besubstituted one to two times by halogen; hydroxy; hydroxy substitutedalkyl; C₁₋₁₀ alkoxy; S(O)_(m)C₁₋₄ alkyl; amino, mono & di-substitutedC₁₋₆ alkyl amino, such as in the NR₄R₁₄ group; C₁₋₄ alkyl, or CF₃.

Preferably, the alkyl chain is branched, such as in t-butyl orisopropyl. More preferably the alkyl chain is substituted one or moretimes, independently by halogen, hydroxy, amino, or mono or di C₁₋₄alkyl substituted amino.

Preferably, when X is the group (CH₂)_(n)NR₂R₄, n is preferably 0 or 1,more preferably 0. The R₂ moiety is preferably, hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted heterocyclic,substituted or unsubstituted heterocyclic alkyl, substituted orunsubstituted heteroaryl, or substituted or unsubstitutedheteroarylalkyl. Such groups preferably include morpholinoethyl,pyrroleethyl, piperidineethyl, pyridylethyl, or piperidine.

Preferably, when X is the group R₂, then R₂ is preferably an optionallysubstituted heteroaryl, such as an imidazole, or tetrazole, or anoptionally substituted heterocyclic ring, such as a pyrrolidine,piperidine, piperazine, or a morpholine ring

As used herein, “optionally substituted” unless specifically definedshall mean, substituent groups which may be substituted on theapplicable moiety one or more times, independently, by halogen, such asfluorine, chlorine, bromine or iodine; hydroxy; hydroxy substitutedC₁₋₁₀alkyl; C₁₋₁₀ alkoxy, such as methoxy or ethoxy; halosubstitutedC₁₋₁₀ alkoxy; S(O)_(m) alkyl, wherein m is 0, 1 or 2, such as methylthio, methylsulfinyl or methyl sulfonyl; NR₄R₁₄, such as amino or monoor -disubstituted C₁₋₄ alkyl or wherein the R₄R₁₄ can cyclize togetherwith the nitrogen to which they are attached to form a 5 to 7 memberedring which optionally contains an additional heteroatom selected fromO/N/S; C₁₋₁₀ alkyl, C₃₋₇cycloalkyl, or C₃₋₇cycloalkyl C₁₋₁₀ alkyl group,such as methyl, ethyl, propyl, isopropyl, t-butyl, etc. or cyclopropylmethyl; halosubstituted C₁₋₁₀ alkyl, such CF₂CF₂H, or CF₃; optionallysubstituted aryl, such as phenyl, or an optionally substitutedarylalkyl, such as benzyl or phenethyl; and wherein the aryl orarylalkyl moieties may also themselves be substituted one to two timesby halogen; hydroxy; hydroxy substituted alkyl; C₁₋₁₀ alkoxy;S(O)_(m)alkyl; amino, mono & di-substituted C₁₋₄ alkyl amino, such as inthe NR₄R₁₄ group; C₁ ₋₄ alkyl, or CF₃.

Suitable pharmaceutically acceptable salts are well known to thoseskilled in the art and include basic salts of inorganic and organicacids, such as hydrochloric acid, hydrobromic acid, sulphuric acid,phosphoric acid, methane sulphonic acid, ethane sulphonic acid, aceticacid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid,succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid,phenylacetic acid and mandelic acid.

In addition, pharmaceutically acceptable salts of compounds of Formulas(I) to (IV) may also be formed with a pharmaceutically acceptablecation, for instance, if a substituent group comprises a carboxy moiety.Suitable pharmaceutically acceptable cations are well known to thoseskilled in the art and include alkaline, alkaline earth, ammonium andquaternary ammonium cations.

The term “halo” or “halogens” is used herein to mean the halogens,chloro, fluoro, bromo and iodo.

The term “C₁₋₁₀alkyl” or “alkyl” or “alkyl₁₋₁₀” is used herein to meanboth straight and branched chain radicals of 1 to 10 carbon atoms,unless the chain length is otherwise limited, including, but not limitedto, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl,tert-butyl, n-pentyl and the like.

The term “cycloalkyl” is used herein to mean cyclic radicals, preferablyof 3 to 8 carbons, including but not limited to, cyclopropyl,cyclopentyl, cyclohexyl, and the like.

The term “cycloalkenyl” is used herein to mean cyclic radicals,preferably of 5 to 8 carbons, which have at least one bond including butnot limited to cyclopentenyl, cyclohexenyl, and the like.

The term “alkenyl” is used herein at all occurrences to mean straight orbranched chain radical of 2-10 carbon atoms, unless the chain length islimited thereto, including, but not limited to ethenyl, 1-propenyl,2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl and the like.

The term “aryl” is used herein to mean phenyl and naphthyl.

The term “heteroaryl” (on its own or in any combination, such as“heteroaryloxy”, or “heteroaryl alkyl”) is used herein to mean a 5-10membered aromatic ring system in which one or more rings contain one ormore heteroatoms selected from the group consisting of N, O or S, suchas, but not limited, to pyrrole, pyrazole, furan, thiophene, quinoline,isoquinoline, quinazolinyl, pyridine, pyrimidine, oxazole, thiazole,thiadiazole, tetrazole, triazole, imidazole, or benzimidazole.

The term “heterocyclic” (on its own or in any combination, such as“heterocyclylalkyl”) is used herein to mean a saturated or partiallyunsaturated 4-10 membered ring system in which one or more rings containone or more heteroatoms selected from the group consisting of N, O, orS; such as, but not limited to, pyrrolidine, piperidine, piperazine,morpholine, tetrahydropyran, or imidazolidine.

The term “aralkyl” or “heteroarylalkyl” or “heterocyclicalkyl” or“cycloalkyl alkyl” or cycloalkenylalkyl” is used herein to mean a C₁₋₄alkyl chain, as defined above, which chain is attached to the respectivearyl, heteroaryl, heterocyclic, cycloalkyl or cycloalkenyl moiety asalso defined herein unless otherwise indicated.

The term “sulfinyl” is used herein to mean the oxide S(O) of thecorresponding sulfide; the term “thio” refers to the sulfide; and theterm “sulfonyl” refers to the fully oxidized S(O)₂ moiety.

The term “aroyl” is used herein to mean C(O)Ar, wherein Ar is as phenyl,naphthyl, or an arylalkyl derivative such as defined above, such groupinclude but are not limited to benzyl and phenethyl.

The term “alkanoyl” is used herein to mean C(O)C₁₋₁₀ alkyl, wherein thealkyl chain is as defined above.

It is recognized that the compounds of the present invention may existas stereoisomers, regioisomers, or diastereiomers. These compounds maycontain one or more asymmetric carbon atoms and may exist in racemic andoptically active forms. All of these compounds are included within thescope of the present invention.

Exemplified compounds of the compounds of Formulas (I) to (IV) and (Ia)to (IVa) include those described in the synthetic examples, and thosenoted below, and their pharmaceutically acceptable salt thereof.

Exemplified compounds of Formula (I), include:7-Methylsulfanyl-5-phenyl-1-(1-phenylethyl)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one

Exemplified compounds of Formula (Ia), include:7-Methylsulfanyl-5-phenyl-1-(1-phenylethyl)-1H-pyrimido[4,5-d]pyrimidin-2-one

Exemplified compounds of Formula (II), include:5-Benzyl-7-(3-morpholin-4-yl-propylamino)-1-phenyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one

Exemplified compounds of Formula (IIa), include:5-Benzyl-7-(3-morpholin-4-yl-propylamino)-1-phenyl-1H-pyrimido[4,5-d]pyrimidin-2-one

Exemplified compounds of Formula (III), include:7-(4-Methyl-piperazin-1-yl)-1,5-diphenyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one

Exemplified compounds of Formula (IIIa), include:7-(4-Methyl-piperazin-1-yl)-1,5-diphenyl-1H-pyrimido[4,5-d]pyrimidin-2-one

Exemplified compounds of Formula (IV), include, but are not limited to,1-(2,6-difluorophenyl)-5-(4-fluoro-2-methylphenyl)-7-methylsulfanyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one;

Exemplified compounds of Formula (IVa), include:7-Methylsulfanyl-1,5-diphenyl-1H-pyrimido[4,5-d]pyrimidin-2-one.

The compounds of Formula (I), (II), (III), (IV) and (V) may be obtainedby applying synthetic procedures, described herein. The synthesisprovided for is applicable to producing compounds of Formula (I) to (V)having a variety of different R₁, R₂, Y, X, and R₃ groups which arereacted, employing optional substituents which are suitably protected,to achieve compatibility with the reactions outlined herein. Subsequentdeprotection, in those cases, then affords compounds of the naturegenerally disclosed.

Once the nucleus has been established, further compounds of Formula (I)may be prepared by applying standard techniques for functional groupinterconversion, well known in the art. For instance: C(O)NR₄R₁₄ fromCO₂CH₃ by heating with or without catalytic metal cyanide, e.g. NaCN,and HNR₄R₁₄ in CH₃OH; OC(O)R₃ from OH with e.g., ClC(O)R₃ in pyridine;NR₁₀—C(S)NR₄R₁₄ from NHR₁₀ with an alkylisothiocyante or thiocyanicacid; NR₁₀C(O)OR₇ from NHR₁₀ with the alkyl chloroformate;NR₁₀C(O)NR₄R₁₄ from NHR₁₀ by treatment with an isocyanate, e.g. HN═C═Oor R₁₀N═C═O; NR₁₀—C(O)R₇ from NHR₁₀ by treatment with Cl—C(O)R₇ inpyridine; C(═NR₁₀)NR₄R₁₄ from C(NR₄R₁₄)SR₃ with H₃NR₃ ⁺OAc⁻ by heatingin alcohol; C(NR₄R₁₄)SR₃ from C(S)NR₄R₁₄ with R₆—I in an inert solvent,e.g. acetone; C(S)NR₄R₁₄ (where R₄ or R₁₄ is not hydrogen) from C(S)NH₂with HNR₄R₁₄—C(═NCN)—NR₄R₁₄ from C(═NR₄R₁₄)—SR₃ with NH₂CN by heating inanhydrous alcohol, alternatively from C(═NH)—NR₄R₁₄ by treatment withBrCN and NaOEt in EtOH; NR₁₀SO₂R₃ from NHR₁₀ by treatment with ClSO₂R₃by heating in pyridine; NR₁₀C(S)R₆ from NR₁₀C(O)R₆ by treatment withLawesson's reagent[2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide];NR₁₀SO₂CF₃ from NHR₆ with triflic anhydride and base wherein R₃, R₆, R₇,R₁₀, R₄ and R₁₄ are as defined in Formula (IV) herein.

Further, other precursors of the various substituent groups herein maybe other groups of compounds of Formula (I) to (V) which may beinterconverted by applying standard techniques for this functional groupinterconversion. Such as use of the S-alkyl intermediate for X incompounds of Formula (IV) which are oxidized and displaced by a suitablenucleophile to yield other final products of Formula (IV). Also forexample, wherein a moiety is a halo substituted C₁₋₁₀ alkyl it can beconverted to the corresponding C₁₋₁₀ alkylN₃ derivative by reacting witha suitable azide salt, and thereafter if desired can be reduced to thecorresponding C₁₋₁₀alkylNH₂ compound, which in turn can be reacted withR₇S(O)₂X wherein X is halo (e.g., chloro) to yield the correspondingC₁₋₁₀alkylNHS(0)₂R₇ compound.

Alternatively wherein the moiety is a halo-substituted C₁₋₁₀-alkyl itcan be reacted with an amine R₄R₁₄NH to yield the correspondingC₁₋₁₀-alkylNR₄R₄ compound, or can be reacted with an alkali metal saltof R₇SH to yield the corresponding C₁₋₁₀alkylSR₇ compound.

Suitable protecting groups for use with hydroxyl groups and nitrogengroups are well known in the art and described in many references, forinstance, Protecting Groups in Organic Synthesis, Greene T W,Wiley-Interscience, New York, 1981. Suitable examples of hydroxylprotecting groups include silyl ethers, such as t-butyldimethyl ort-butyldiphenyl, and alkyl ethers, such as methyl connected by an alkylchain of variable link, (CR₁₀R₂₀)_(n).

Pharmaceutically acid addition salts of compounds of Formula (I) to (V),and (Ia) to (Va) may be obtained in known manner, for example bytreatment thereof with an appropriate amount of acid in the presence ofa suitable solvent.

In Schemes I and II herein, X₁ is a C₁₋₁₀ alkyl, aryl, or heteroarylgroup, and Y—R₁ is as defined for Formula (IV) compounds.

Commercially available 4,6-dihydroxy-2-methylmercaptopyrimidine (1)(which can also be prepared by the literature methods and utilized asdescribed below, with S-alkyl other than S-methyl or S-aryl) wasconverted to the nitrile (3) by the literature procedure [see Santilli,et al., J. Heterocycl. Chem. 1971, 8, 445-453] (Scheme 1). Compound 3reacts with one equivalent of amine by procedures analogous to thosedescribed for related compounds, to afford the2-methylsulfanyl-4-chloro-6-amino-pyrimidine-5-carbonitrile (4) [SeeTumkevicius, S. Liebigs Ann. 1995, 1703-1705].

The Suzuki reaction of 4 with aryl boronic acids using a palladiumcatalyst, such as, tetrakis(triphenylphosphine) palladium(0) catalystproceeds in good to excellent yield. Alternatively, the bi-aryl couplingreaction of (4) can be performed using aryl or heteroaryl organozinc,organcopper, organotin, or other organometallic reagents known to affordbi-aryl cross-coupling products [See for example Solberg, J.; Undheim,K. Acta Chemica Scandinavia 1989, 62-68]. Displacement of the chlorinein 4 may also be achieved with nitrogen nucleophiles [For relatedaminations see U.S. Pat. Nos. 3,631,045 and 3,910,913]. Displacment ofthe chlorine in 4 is also possible with S nucleophiles, [SeeTumkevicius, S. Liebigs Ann. 1995, 1703-1705] or O, or alkylnucleophiles.

The7-methylsufamyl-1,5-disubstituted-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-ones(7) are prepared by reduction of the nitriles (5) preferably with ahydride reducing agent, such as lithium aluminum hydride or NaB₂H₇preferably in an ethereal solvent, such as THF, Et₂O, glyme or dioxaneto produce the di-amine (6). In cases where functionality isincompatible with the more reactive hydride reducing agents,alternative, selective, reduction methods for the nitriles includesamarium di-iodide in H₃PO₄, Raney Ni catalyzed hydrogenation, or sodiumborohydride-cobaltous chloride. The resulting diamines 6 can be cyclizedto (7) with carbonyldiimidazole or a mixed anhydride such as ethylchloroformate, or for less reactive diamines, with phosgene ortriphosgene and a suitable tertiary amine base at temperatures between−78° and 100° C.

Oxidation of the sulfides (7) with an oxidant such as one or twoequivalents of meta-chloroperoxybenzoic acid or Oxone affords either thesulfoxides or sulfones. Oxidation of the sulfides to sulfones can alsobe effected by OsO₄ and catalytic tertiary amine N-oxide. Other methodsfor sulfide oxidation include the use of hydrogen peroxide, otherperacids, oxygen, ozone, organic peroxides, potassium and zincpermanganate, potassium persulfate, and sodium hypochlorite.

Both 2-pyrimidininyl sulfones and sulfoxides related to compounds ofFormula (IV) wherein X is SO-alkyl or SO₂-alkyl have been reported inthe literature to be displaced by a wide variety of nucleophiles. Thusthe analogs of Formula (IV) compounds wherein X is an alkyl sulfone orsulfoxide may be displaced by primary and secondary alkylamines withoutadditional base catalysis, preferably in a polar aprotic solvent, suchas but not limited to, N-methylpyrrolidin-2-one (NMP), and at varyingtemperatures depending upon the nucleophilicity of the amine. Forinstance displacement of the sulfone of analogs of Formula (IV)compounds with ethanolamine, in NMP, occurs in 30 min. at about 65°while a more hindered amine such as Tris(hydroxymethyl)aminomethanerequires elevated temperatures and extended reaction times (such as,about 80° and about a 24 hour reaction time). The sulfone may also bedisplaced with substituted arylamine, or heteroarylamines at elevatedtemperatures, sometimes requiring formation of the aryl orheteroarylamine anion as with sodium hydride, or other suitable base, inDMSO. In addition, the sulfoxide analogs of Formula (IV) compounds maybe readily displaced with aluminum salts of aryl or heteroaryl amines aspreviously described in the patent literature (WO 9932121).

Likewise, sulfone and sulfoxide analogs of (IV) may be displaced witharyl or heteroaryl or alkyl thiols or alkyl or aryl or heteroarylalcohols. For instance analogs of IV containing sulfones as the Xsubstituents may be displaced with sodium alkoxide in the alcohol oralternatively reactive alkoxide or phenoxide nucleophiles may begenerated from the alcohol or phenol with a suitable base such as NaH orsodium bis-trimethylsilyl amide in a polar aprotic solvent such as DMSO.

Similarly 2-pyrimidinyl sulfones related to (IV) may be displaced withcarbon nucleophiles such as aryl or alkyl Grignard reagents or relatedorganometalics such as organo lithium, zinc, tin or boron. Thesereactions may, in some cases, require transition metal catalysis such aswith Pd or Ni catalysts. Displacement of related 2-pyrimidine sulfoneswith cyanide, malonate anions, unactivated enolates, or heterocyclic Cnucleophiles such as 1-methylimidazole anion, by the generation of theanion with NaH or other suitable base in THF also has precedent (see forexample, Chem Pharm Bull. 1987, 4972-4976.). For example analogs of (IV)compounds wherein X is an alkyl sulfone may be displaced with the anionof 1-methyl imidazole, generated by treatment of 1-methyl imidazole withn -butyl lithium in a solvent such as THF at temperatures of about −70°,to afford the C -alkylated product substituted on the imidazole C-2.

The 3,4-Dihydro-1H-pyrimido[4,5-d]pyrimidin-2-ones, unsubstituted at the7 position (9) (Scheme 1) can be obtained by Raney Ni hydrogenolysis ofthe SMe compound (7) as well as by direct synthesis from the analog of 1(in Scheme 1) which lacks the S alkyl substituent.

The oxidized series of analogs of Formula (IVa) compounds may beprepared from 5 by partial reduction of the nitrile with a suitablehydride reducing agent such as diisobutylaluminum hydride, preferably atlow temperature, and avoiding hydrolytic conditions, to afford the imine(Scheme 2). Cyclization of the imine with phosgene or a less reactiveequivalent of phosgene such as carbonyldiimidazole affords 1a (Scheme2).

Substitution at the 7 position of the3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-ones with aryl substituents isalso readily achieved by performing the 2-aryl pyrimidines as depictedin Scheme 3 below. While the scheme displays R₁ and X as an aryl moiety,it is merely for representation purposes herein.

Another aspect of the present invention are the intermediate compoundsof Formula (A):

wherein Y—R₁ and R₃ are as defined herein for Formula (IV); and X₁ is aC₁₋₁₀ alkyl, aryl or heteroaryl moiety. Preferably X₁ is a C₁₋₁₀ alkyl,more preferably a methyl or propyl.

Another aspect of the present invention are the intermediate compoundsof Formula (C):

wherein Y—R₁ and R₃ are as defined herein for Formula (IV); and X₁ is aC₁₋₁₀ alkyl, aryl or heteroaryl moiety. Preferably X₁ is a C₁₋₁₀ alkyl,more preferably a methyl or propyl.Methods of Treatment

The compounds of Formula (I) to (V) and (Ia) to (Va) or apharmaceutically acceptable salt thereof can be used in the manufactureof a medicament for the prophylactic or therapeutic treatment of anydisease state in a human, or other mammal, which is exacerbated orcaused by excessive or unregulated cytokine production by such mammal'scell, such as but not limited to monocytes and/or macrophages; or by theexacerbation or excessive or unregulated production of the CSBP protein.

For purposes herein, compounds of Formula (I) to (V) and (Ia) to (Va)will all be referred to as compounds of Formula (I) unless otherwiseindicated.

Compounds of Formula (I) are capable of inhibiting proinflammatorycytokines, such as IL-1, IL-6, IL-8, and TNF and are therefore of use intherapy. IL-1, IL-6, IL-8 and TNF affect a wide variety of cells andtissues and these cytokines, as well as other leukocyte-derivedcytokines, are important and critical inflammatory mediators of a widevariety of disease states and conditions. The inhibition of thesepro-inflammatory cytokines is of benefit in controlling, reducing andalleviating many of these disease states.

Accordingly, the present invention provides a method of treating acytokine-mediated disease which comprises administering an effectivecytokine-interfering amount of a compound of Formula (I) or apharmaceutically acceptable salt thereof.

Compounds of Formula (I) are capable of inhibiting inducibleproinflammatory proteins, such as COX-2, also referred to by many othernames such as prostaglandin endoperoxide synthase-2 (PGHS-2) and aretherefore of use in therapy. These proinflammatory lipid mediators ofthe cyclooxygenase (CO) pathway are produced by the inducible COX-2enzyme. Regulation, therefore of COX-2 which is responsible for thethese products derived from arachidonic acid, such as prostaglandinsaffect a wide variety of cells and tissues are important and criticalinflammatory mediators of a wide variety of disease states andconditions. Expression of COX-1 is not effected by compounds of Formula(I). This selective inhibition of COX-2 may alleviate or spareulcerogenic liability associated with inhibition of COX-1 therebyinhibiting prostoglandins essential for cytoprotective effects. Thusinhibition of these pro-inflammatory mediators is of benefit incontrolling, reducing and alleviating many of these disease states. Mostnotably these inflammatory mediators, in particular prostaglandins, havebeen implicated in pain, such as in the sensitization of pain receptors,or edema. This aspect of pain management therefore includes treatment ofneuromuscular pain, headache, cancer pain, and arthritis pain. Compoundsof Formula (I) or a pharmaceutically acceptable salt thereof, are of usein the prophylaxis or therapy in a human, or other mammal, by inhibitionof the synthesis of the COX-2 enzyme.

Accordingly, the present invention provides a method of inhibiting thesynthesis of COX-2 which comprises administering an effective amount ofa compound of Formula (I) or a pharmaceutically acceptable salt thereof.The present invention also provides for a method of prophylaxistreatment in a human, or other mammal, by inhibition of the synthesis ofthe COX-2 enzyme.

In particular, compounds of Formula (I) or a pharmaceutically acceptablesalt thereof are of use in the prophylaxis or therapy of any diseasestate in a human, or other mammal, which is exacerbated by or caused byexcessive or unregulated IL-1, IL-6, IL-8 or TNF production by suchmammal's cell, such as, but not limited to, monocytes and/ormacrophages.

Accordingly, in another aspect, this invention relates to a method ofinhibiting the production of IL-1 in a mammal in need thereof whichcomprises administering to said mammal an effective amount of a compoundof Formula (I) or a pharmaceutically acceptable salt thereof.

There are many disease states in which excessive or unregulated IL-1production is implicated in exacerbating and/or causing the disease.These include rheumatoid arthritis, osteoarthritis, meningitis, ischemicand hemorrhagic stroke, neurotrauma/closed head injury, stroke,endotoxemia and/or toxic shock syndrome, other acute or chronicinflammatory disease states such as the inflammatory reaction induced byendotoxin or inflammatory bowel disease, tuberculosis, atherosclerosis,muscle degeneration, multiple sclerosis, cachexia, bone resorption,psoriatic arthritis, Reiter's syndrome, rheumatoid arthritis, gout,traumatic arthritis, rubella arthritis and acute synovitis. Recentevidence also links IL-1 activity to diabetes, pancreatic β celldiseases and Alzheimer's disease.

Use of a CSAID for the treatment of CSBP mediated disease states, caninclude, but not be limited to neurodegenerative diseases, such asAlzheimer's disease (as noted above), Parkinson's disease and multiplesclerosis, etc.

In a further aspect, this invention relates to a method of inhibitingthe production of TNF in a mammal in need thereof which comprisesadministering to said mammal an effective amount of a compound ofFormula (I) or a pharmaceutically acceptable salt thereof.

Excessive or unregulated TNF production has been implicated in mediatingor exacerbating a number of diseases including rheumatoid arthritis,rheumatoid spondylitis, osteoarthritis, gouty arthritis and otherarthritic conditions, sepsis, septic shock, endotoxic shock, gramnegative sepsis, toxic shock syndrome, adult respiratory distresssyndrome, chronic pulmonary inflammatory disease and chronic obstructivepulmonary disease, silicosis, pulmonary sarcoisosis, bone resorptiondiseases, such as osteoporosis, cardiac, brain and renal reperfusioninjury, graft vs. host reaction, allograft rejections, fever andmyalgias due to infection, such as influenza, brain infections includingencephalitis (including HIV-induced forms), cerebral malaria,meningitis, ischemic and hemorrhagic stroke, cachexia secondary toinfection or malignancy, cachexia secondary to acquired immunedeficiency syndrome (AIDS), AIDS, ARC (AIDS related complex), keloidformation, scar tissue formation, inflammatory bowel disease, Crohn'sdisease, ulcerative colitis and pyresis.

Compounds of Formula (I) are also useful in the treatment of viralinfections, where such viruses are sensitive to upregulation by TNF orwill elicit TNF production in vivo. The viruses contemplated fortreatment herein are those that produce TNF as a result of infection, orthose which are sensitive to inhibition, such as by decreasedreplication, directly or indirectly, by the TNF inhibiting-compounds ofFormula (I). Such viruses include, but are not limited to HIV-1, HIV-2and HIV-3, Cytomegalovirus (CMV), Influenza, adenovirus and the Herpesgroup of viruses, such as but not limited to, Herpes Zoster and HerpesSimplex. Accordingly, in a further aspect, this invention relates to amethod of treating a mammal afflicted with a human immunodeficiencyvirus (HIV) which comprises administering to such mammal an effectiveTNF inhibiting amount of a compound of Formula (I) or a pharmaceuticallyacceptable salt thereof.

It is also recognized that both IL-6 and IL-8 are produced duringrhinovirus (HRV) infections and contribute to the pathogenesis of commoncold and exacerbation of asthma associated with HRV infection (Turner etal., (1998), Clin. Infec. Dis., Vol 26, p 840; Teren et al., (1997), AmJ Respir Crit. Care Med vol 155, p1362; Grunberg et al. (1997), Am JRespir Crit. Care Med 156:609 and Zhu et al, J Clin Invest (1996),97:421). It has also been demonstrated in vitro that infection ofpulmonary epithelial cells with HRV results in production of IL-6 andIL-8 (Subauste et al., J. Clin. Invest. 1995, 96:549.) Epithelial cellsrepresent the primary site of infection of HRV. Therefore another aspectof the present invention is a method of treatment to reduce inflammationassociated with a rhinovirus infection, not necessarily a direct effecton virus itself.

Compounds of Formula (I) may also be used in association with theveterinary treatment of mammals, other than in humans, in need ofinhibition of TNF production. TNF mediated diseases for treatment,therapeutically or prophylactically, in animals include disease statessuch as those noted above, but in particular viral infections. Examplesof such viruses include, but are not limited to, lentivirus infectionssuch as, equine infectious anaemia virus, caprine arthritis virus, visnavirus, or maedi virus or retrovirus infections, such as but not limitedto feline immunodeficiency virus (FIV), bovine immunodeficiency virus,or canine immunodeficiency virus or other retroviral infections.

The compounds of Formula (I) may also be used topically in the treatmentor prophylaxis of topical disease states mediated by or exacerbated byexcessive cytokine production, such as by IL-1 or TNF respectively, suchas inflamed joints, eczema, psoriasis and other inflammatory skinconditions such as sunburn; inflammatory eye conditions includingconjunctivitis; pyresis, pain and other conditions associated withinflammation. Periodontal disease has also been implemented in cytokineproduction, both topically and systemically. Hence use of compounds ofFormula (I) to control the inflammation associated with cytokineproduction in such peroral diseases such as gingivitis and periodontitisis another aspect of the present invention.

Compounds of Formula (I) have also been shown to inhibit the productionof IL-8 (Interleukin-8, NAP). Accordingly, in a further aspect, thisinvention relates to a method of inhibiting the production of IL-8 in amammal in need thereof which comprises administering to said mammal aneffective amount of a compound of Formula (I) or a pharmaceuticallyacceptable salt thereof.

There are many disease states in which excessive or unregulated IL-8production is implicated in exacerbating and/or causing the disease.These diseases are characterized by massive neutrophil infiltration suchas, psoriasis, inflammatory bowel disease, asthma, cardiac, brain andrenal repeRtusion injury, adult respiratory distress syndrome,thrombosis and glomerulonephritis. All of these diseases are associatedwith increased IL-8 production which is responsible for the chemotaxisof neutrophils into the inflammatory site. In contrast to otherinflammatory cytokines (IL-1, TNF, and IL-6), IL-8 has the uniqueproperty of promoting neutrophil chemotaxis and activation. Therefore,the inhibition of IL-8 production would lead to a direct reduction inthe neutrophil infiltration.

The compounds of Formula (I) are administered in an amount sufficient toinhibit cytokine, in particular IL-1, IL-6, IL-8 or TNF, production suchthat it is regulated down to normal levels, or in some case to subnormallevels, so as to ameliorate or prevent the disease state. Abnormallevels of IL-1, IL-6, IL-8 or TNF, for instance in the context of thepresent invention, constitute: (i) levels of free (not cell bound) IL-1,IL-6, IL-8 or TNF greater than or equal to 1 picogram per ml; (ii) anycell associated IL-1, IL-6, IL-8 or TNF; or (iii) the presence of IL-1,IL-6, IL-8 or TNF mRNA above basal levels in cells or tissues in whichIL-1, IL-6, IL-8 or TNF, respectively, is produced.

The discovery that the compounds of Formula (I) are inhibitors ofcytokines, specifically IL-1, IL-6, IL-8 and TNF is based upon theeffects of the compounds of Formulas (I) on the production of the IL-1,IL-8 and TNF in in vitro assays which are described herein.

As used herein, the term “inhibiting the production of IL-1 (IL-6, IL-8or TNF)” refers to:

a) a decrease of excessive in vivo levels of the cytokine (IL-1, IL-6,IL-8 or TNF) in a human to normal or sub-normal levels by inhibition ofthe in release of the cytokine by all cells, including but not limitedto monocytes or macrophages;

b) a down regulation, at the genomic level, of excessive in vivo levelsof the cytokine (IL-1, IL-6, IL-8 or TNF) in a human to normal orsub-normal levels;

c) a down regulation, by inhibition of the direct synthesis of thecytokine (IL-1, IL-6, IL-8 or TNF) as a posttranslational event; or

d) a down regulation, at the translational level, of excessive in vivolevels of the cytokine (IL-1, IL-6, IL-8 or TNF) in a human to normal orsub-normal levels.

As used herein, the term “TNF mediated disease or disease state” refersto any and all disease states in which TNF plays a role, either byproduction of TNF itself, or by TNF causing another monokine to bereleased, such as but not limited to IL-1, IL-6 or IL-8. A disease statein which, for instance, IL-1 is a major component, and whose productionor action, is exacerbated or secreted in response to TNF, wouldtherefore be considered a disease stated mediated by TNF.

As used herein, the term “cytokine” refers to any secreted polypeptidethat affects the functions of cells and is a molecule which modulatesinteractions between cells in the immune, inflammatory or hematopoieticresponse. A cytokine includes, but is not limited to, monokines andlymphokines, regardless of which cells produce them. For instance, amonokine is generally referred to as being produced and secreted by amononuclear cell, such as a macrophage and/or monocyte. Many other cellshowever also produce monokines, such as natural killer cells,fibroblasts, basophils, neutrophils, endothelial cells, brainastrocytes, bone marrow stromal cells, epideral keratinocytes andB-lymphocytes. Lymphokines are generally referred to as being producedby lymphocyte cells. Examples of cytokines include, but are not limitedto, Interleukin-1 (IL-1), Interleukin-6 (IL-6), Interleukin-8 (IL-8),Tumor Necrosis Factor-alpha (TNF-a) and Tumor Necrosis Factor beta(TNF-β). As used herein, the term “cytokine interfering” or “cytokinesuppressive amount” refers to an effective amount of a compound ofFormula (I) which will cause a decrease in the in vivo levels of thecytokine to normal or sub-normal levels, when given to a patient for theprophylaxis or treatment of a disease state which is exacerbated by, orcaused by, excessive or unregulated cytokine production.

As used herein, the cytokine referred to in the phrase “inhibition of acytokine, for use in the treatment of a HIV-infected human” is acytokine which is implicated in (a) the initiation and/or maintenance ofT cell activation and/or activated T cell-mediated HIV gene expressionand/or replication and/or (b) any cytokine-mediated disease associatedproblem such as cachexia or muscle degeneration.

As TNF-β (also known as lymphotoxin) has close structural homology withTNF-α (also known as cachectin) and since each induces similar biologicresponses and binds to the same cellular receptor, both TNF-α and TNF-βare inhibited by the compounds of the present invention and thus areherein referred to collectively as “TNF” unless specifically delineatedotherwise.

A member of the MAP kinase family, alternatively termed CSBP, p38, orRK, has been identified independently by several laboratories.Activation of this novel protein kinase via dual phosphorylation hasbeen observed in different cell systems upon stimulation by a widespectrum of stimuli, such as physicochemical stress and treatment withlipopolysaccharide or proinflammatory cytokines such as interleukin-1and tumor necrosis factor. The cytokine biosynthesis inhibitors, of thepresent invention, compounds of Formula (I) have been determined to bepotent and selective inhibitors of CSBP/p38/RK kinase activity. Theseinhibitors are of aid in determining the signaling pathways involvementin inflammatory responses. In particular, for the first time adefinitive signal transduction pathway can be prescribed to the actionof lipopolysaccharide in cytokine production in macrophages. In additionto those diseases already noted, treatment of stroke, neurotrauma,cardiac and renal reperfusion injury, congestive heart failure, coronaryarterial bypass grafting (CABG) surgery, chronic renal failure,angiogenesis & related processes, such as cancer, thrombosis,glomerulonephritis, diabetes and pancreatic β cells, multiple sclerosis,muscle degeneration, eczema, psoriasis, sunburn, and conjunctivitis arealso included.

The CSBP inhibitors were subsequently tested in a number of animalmodels for anti-inflammatory activity. Model systems were chosen thatwere relatively insensitive to cyclooxygenase inhibitors in order toreveal the unique activities of cytokine suppressive agents. Theinhibitors exhibited significant activity in many such in vivo studies.Most notable are its effectiveness in the collagen-induced arthritismodel and inhibition of TNF production in the endotoxic shock model. Inthe latter study, the reduction in plasma level of TNF correlated withsurvival and protection from endotoxic shock related mortality. Also ofgreat importance are the compounds effectiveness in inhibiting boneresorption in a rat fetal long bone organ culture system. Griswold etal., (1988) Arthritis Rheum. 31:1406-1412; Badger, et al., (1989) Circ.Shock 27, 51-61; Votta et al., (1994) in vitro. Bone 15, 533-538; Lee etal., (1993). B Ann. N.Y. Acad. Sci. 696, 149-170.

Chronic diseases which have an inappropriate angiogenic component arevarious ocular neovasularizations, such as diabetic retinopathy andmacular degeneration. Other chronic diseases which have an excessive orincreased proliferation of vasculature are tumor growth and metastasis,atherosclerosis, and certain arthritic conditions. Therefore CSBP kinaseinhibitors will be of utility in the blocking of the angiogeniccomponent of these disease states.

The term “excessive or increased proliferation of vasculatureinappropriate angiogenesis” as used herein includes, but is not limitedto, diseases which are characterized by hemangiomas and ocular diseases.

The term “inappropriate angiogenesis” as used herein includes, but isnot limited to, diseases which are characterized by vesicleproliferation with accompanying tissue proliferation, such as occurs incancer, metastasis, arthritis and atherosclerosis.

Another aspect of the present invention is a method of treating thecommon cold or respiratory viral infection caused by human rhinovirus(HRV), other enteroviruses, coronavirus, influenza virus, parainfluenzavirus, respiratory syncytial virus, or adenovirus in a human in needthereof which method comprises administering to said human an effectiveamount of a CBSP/p38 inhibitor.

Another aspect of the present invention is a method of treating,including prophylaxis of influenza induced pneumonia in a human in needthereof which method comprises administering to said human an effectiveamount of a CBSP/p38 inhibitor

The present invention also relates to the use of the CSBP/p38 kinaseinhibitor for the treatment, including prophylaxis, of inflammationassociated with a viral infection of a human rhinovirus (HRV), otherenteroviruses, coronavirus, influenza virus, parainfluenza virus,respiratory syncytial virus, or adenovirus.

In particular, the present invention is directed to the treatment of aviral infection in a human, which is caused by the human rhinovirus(HRV), other enterovirus, coronavirus, influenza virus, parainfluenzavirus, respiratory syncytial virus, or an adenovirus. In particular theinvention is directed to respiratory viral infections that exacerbateasthma (induced by such infections), chronic bronchitis, chronicobstructive pulmonary disease, otitis media, and sinusitis. Whileinhibiting IL-8 or other cytokines may be beneficial in treating arhinovirus may be known, the use of an inhibitor of the p38 kinase fortreating HRV or other respiratory viral infections causing the commoncold is believed novel.

It should be noted that the respiratory viral infection treated hereinmay also be associated with a secondary bacterial infection, such asotitis media, sinusitis, or pneumonia.

For use herein treatment may include prophylaxis for use in a treatmentgroup susceptible to such infections. It may also include reducing thesymptoms of, ameliorating the symptoms of, reducing the severity of,reducing the incidence of, or any other change in the condition of thepatient, which improves the therapeutic outcome.

It should be noted that the treatment herein is not directed to theelimination or treatment of the viral organism itself but is directed totreatment of the respiratory viral infection that exacerbates otherdiseases or symptoms of disease, such as asthma (induced by suchinfections), chronic bronchitis, chronic obstructive pulmonary disease,otitis media, and sinusitis.

A preferred virus for treatment herein is the human rhinovirus infection(HRV) or respiratory syncytial virus (RSV).

Another aspect of the present invention is directed to the treatment ofinhaled smoke induced airway inflammation, lung chemokine production andcytokine production. The invention may be directed to treatment of theairway induced inflammation which is secondary to other respiratorydisorders such as viral infections that exacerbate asthma (induced bysuch infections), chronic bronchitis, chronic obstructive pulmonarydisease, otitis media, and sinusitis. A respiratory viral infectiontreated in conjunction with the smoke related airway inflammation mayalso be associated with a secondary bacterial infection, such as otitismedia, sinusitis, or pneumonia.

It is noted that the inflammation may be due to cytokines and chemokinerelease from neutrophile activation and other leukocytes, as well asvascular and airway endothelial cell activation.

For use herein treatment may include prophylaxis for use in a treatmentgroup who may be susceptible to such airway inflammation. It may alsoinclude reducing the symptoms of, ameliorating the symptoms of, reducingthe severity of, reducing the incidence of, or any other change in thecondition of the patient, which improves the therapeutic outcome.

Suitable patient populations for whom this may be prophylacticallybeneficial could be firemen who routinely inhale smoke in the course oftheir duties; use in the military, and by civilians in wartime exposure.

As noted, smoke of natural causes, such as plant extracts, naturalplants products, synthetic material, chemically treated naturalmaterials, or natural products such as oil and gas or other fossilfuels, may be treated within the scope of this invention. Suitably, thetreatment including prophylaxis is related to cigarette smoke orsynthetic/composites, such as occur in fires associated with burningbuildings or homes.

Another aspect of the present invention relates to the use of a CSBP/p38kinase inhibitor for the treatment, including prophylaxis, of thehypertussive activity associated with resulting airway inflammationand/or cough in a mammal in need thereof.

The present invention also relates to use of a CSBP/p38 kinase inhibitorfor the treatment, including prophylaxis, of the inflammation enhancedcough related disorders in a mammal in need thereof.

The present invention is also directed to the use of a compound ofFormula (I) in eosinophilic bronchitis, and in cough variant asthma.

The compounds of Formula (I) may also be used in the treatment,including prophylaxis, of eosinophilic inflammation in the airways andcough. Treatment, including prophylaxis is appropriate for eosinophilicbronchitis (as this differs from asthma) and for the treatment,including prophylaxis of cough variant asthma. These disorders may bedirected to treatment of the airway induced inflammation which issecondary to other respiratory disorders such as viral infections thatexacerbate asthma (induced by such infections), chronic bronchitis,chronic obstructive pulmonary disease, otitis media, and sinusitis. Arespiratory viral infection treated in conjunction with the smokerelated airway inflammation may also be associated with a secondarybacterial infection, such as otitis media, sinusitis, or pneumonia.

The hypertussive or inflammation enhanced cough related disorders mayeither be a direct result of or an association with eosinophiliaactivity. It may also be a result of, or associated with the blockingproduction of certain cytokines which may mediate these phenomena.

For use herein treatment may include prophylaxis for use in a treatmentgroup who may be susceptible to such airway inflammation, and/or cough.It may also include reducing the symptoms of, ameliorating the symptomsof, reducing the severity of, reducing the incidence of, or any otherchange in the condition of the patient, which improves the therapeuticoutcome.

Clinically, eosinophilic bronchitis presents as chronic cough and sputumeosinophilia, but without the abnormalities of airway function seen inasthma. In contrast to cough in patients without sputum eosinophilia,the cough responds to anti-inflammatory therapy, such as inhaledcorticosteroids (Niimi et al., Eosinophilic inflammation in coughvariant asthma, European Respiratory Journal. 11 (5): 1064-9, (1998)).

Patients with cough-variant asthma may also have the following criteria:(1) have not been previously diagnosed as having asthma; (2) complain ofa cough of at least a 3-week duration; (3) do not complain of wheezing,shortness of breath, or chest tightness; (4) have normal results ofphysical examinations; (5) have normal or nearly normal results ofspirometry; (6) have evidence of bronchial hyperresponsiveness duringbronchoprovocation challenge testing; and (7) have a favorable responseto asthma medications (Irwin et al., Interpretation of positive resultsof a methacholine inhalation challenge and 1 week of inhaledbronchodilator use in diagnosing and treating cough-variant asthma(Archives of Internal Medicine. 157(17):1981-1987, (1997)).

Unlike conventional anti-tussive agents, such as codeine ordextromethorphan, a p38 kinase inhibitor appears to have no directantitussive activity, but reduces the airway eosinophilia and normalizesthe hypertussive state. Therefore, use of a p38 inhibitor will reducethe added coughs, or hypertussive state, back to a normal level whichcan be suitably treated with conventional agents and/or therapies asappropriate. Use of the p38 inhibitors will allow for the maintenance ofpatients who are subject to increased cough responsiveness, especiallyunproductive cough, due to other underlying disorders or treatments.This increased cough responsiveness may be modulated, or decreased byuse of this innovative anti-inflammatory therapy.

Accordingly, the present invention provides a method of treating a CSBPkinase mediated disease in a mammal in need thereof, preferably a human,which comprises administering to said mammal, an effective amount of acompound of Formula (I) or a pharmaceutically acceptable salt thereof.

In order to use a compound of Formula (I) or a pharmaceuticallyacceptable salt thereof in therapy, it will normally be formulated intoa pharmaceutical composition in accordance with standard pharmaceuticalpractice. This invention, therefore, also relates to a pharmaceuticalcomposition comprising an effective, non-toxic amount of a compound ofFormula (I) and a pharmaceutically acceptable carrier or diluent.

Compounds of Formula (I), pharmaceutically acceptable salts thereof andpharmaceutical compositions incorporating such may conveniently beadministered by any of the routes conventionally used for drugadministration, for instance, orally, topically, parenterally or byinhalation. The compounds of Formula (I) may be administered inconventional dosage forms prepared by combining a compound of Formula(I) with standard pharmaceutical carriers according to conventionalprocedures. The compounds of Formula (I) may also be administered inconventional dosages in combination with a known, second therapeuticallyactive compound. These procedures may involve mixing, granulating andcompressing or dissolving the ingredients as appropriate to the desiredpreparation. It will be appreciated that the form and character of thepharmaceutically acceptable character or diluent is dictated by theamount of active ingredient with which it is to be combined, the routeof administration and other well-known variables. The carrier(s) must be“acceptable” in the sense of being compatible with the other ingredientsof the formulation and not deleterious to the recipient thereof.

The pharmaceutical carrier employed may be, for example, either a solidor liquid. Exemplary of solid carriers are lactose, terra alba, sucrose,talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acidand the like. Exemplary of liquid carriers are syrup, peanut oil, oliveoil, H₂O and the like. Similarly, the carrier or diluent may includetime delay material well known to the art, such as glycerylmono-stearate or glyceryl distearate alone or with a wax.

A wide variety of pharmaceutical forms can be employed. Thus, if a solidcarrier is used, the preparation can be tableted, placed in a hardgelatin capsule in powder or pellet form or in the form of a troche orlozenge. The amount of solid carrier will vary widely but preferablywill be from about 25 mg. to about 1 g. When a liquid carrier is used,the preparation will be in the form of a syrup, emulsion, soft gelatincapsule, sterile injectable liquid such as an ampule or nonaqueousliquid suspension.

Compounds of Formula (I) may be administered topically, that is bynon-systemic administration. This includes the application of a compoundof Formula (I) externally to the epidermis or the buccal cavity and theinstillation of such a compound into the ear, eye and nose, such thatthe compound does not significantly enter the blood stream. In contrast,systemic administration refers to oral, intravenous, intraperitoneal andintramuscular administration.

Formulations suitable for topical administration include liquid orsemi-liquid preparations suitable for penetration through the skin tothe site of inflammation such as liniments, lotions, creams, ointmentsor pastes, and drops suitable for administration to the eye, ear ornose. The active ingredient may comprise, for topical administration,from 0.001% to 10% w/w, for instance from 1% to 2% by weight of theformulation. It may however comprise as much as 10% w/w but preferablywill comprise less than 5% w/w, more preferably from 0.1% to 1% w/w ofthe formulation.

Lotions according to the present invention include those suitable forapplication to the skin or eye. An eye lotion may comprise a sterileaqueous solution optionally containing a bactericide and may be preparedby methods similar to those for the preparation of drops. Lotions orliniments for application to the skin may also include an agent tohasten drying and to cool the skin, such as an alcohol or acetone,and/or a moisturizer such as glycerol or an oil such as castor oil orarachis oil.

Creams, ointments or pastes according to the present invention aresemi-solid formulations of the active ingredient for externalapplication. They may be made by mixing the active ingredient infinely-divided or powdered form, alone or in solution or suspension inan aqueous or non-aqueous fluid, with the aid of suitable machinery,with a greasy or non-greasy base. The base may comprise hydrocarbonssuch as hard, soft or liquid paraffin, glycerol, beeswax, a metallicsoap; a mucilage; an oil of natural origin such as almond, corn,arachis, castor or olive oil; wool fat or its derivatives or a fattyacid such as steric or oleic acid together with an alcohol such aspropylene glycol or a macrogel. The formulation may incorporate anysuitable surface active agent such as an anionic, cationic or non-ionicsurfactant such as a sorbitan ester or a polyoxyethylene derivativethereof. Suspending agents such as natural gums, cellulose derivativesor inorganic materials such as silicaceous silicas, and otheringredients such as lanolin, may also be included.

Drops according to the present invention may comprise sterile aqueous oroily solutions or suspensions and may be prepared by dissolving theactive ingredient in a suitable aqueous solution of a bactericidaland/or fungicidal agent and/or any other suitable preservative, andpreferably including a surface active agent. The resulting solution maythen be clarified by filtration, transferred to a suitable containerwhich is then sealed and sterilized by autoclaving or maintaining at98-100° C. for half an hour. Alternatively, the solution may besterilized by filtration and transferred to the container by an aseptictechnique. Examples of bactericidal and fungicidal agents suitable forinclusion in the drops are phenylmercuric nitrate or acetate (0.002%),benzalkonium chloride (0.01%) and chlorhexidine acetate (0.01%).Suitable solvents for the preparation of an oily solution includeglycerol, diluted alcohol and propylene glycol.

Compounds of Formula (I) may be administered parenterally, that is byintravenous, intramuscular, subcutaneous intranasal, intrarectal,intravaginal or intraperitoneal administration. The subcutaneous andintramuscular forms of parenteral administration are generallypreferred. Appropriate dosage forms for such administration may beprepared by conventional techniques. Compounds of Formula (I) may alsobe administered by inhalation, that is by intranasal and oral inhalationadministration. Appropriate dosage forms for such administration, suchas an aerosol formulation or a metered dose inhaler, may be prepared byconventional techniques.

For all methods of use disclosed herein for the compounds of Formula(I), the daily oral dosage regimen will preferably be from about 0.1 toabout 80 mg/kg of total body weight, preferably from about 0.2 to 30mg/kg, more preferably from about 0.5 mg to 15 mg. The daily parenteraldosage regimen about 0.1 to about 80 mg/kg of total body weight,preferably from about 0.2 to about 30 mg/kg, and more preferably fromabout 0.5 mg to 15 mg/kg. The daily topical dosage regimen willpreferably be from 0.1 mg to 150 mg, administered one to four,preferably two or three times daily. The daily inhalation dosage regimenwill preferably be from about 0.01 mg/kg to about 1 mg/kg per day. Itwill also be recognized by one of skill in the art that the optimalquantity and spacing of individual dosages of a compound of Formula (I)or a pharmaceutically acceptable salt thereof will be determined by thenature and extent of the condition being treated, the form, route andsite of administration, and the particular patient being treated, andthat such optimums can be determined by conventional techniques. It willalso be appreciated by one of skill in the art that the optimal courseof treatment, i.e., the number of doses of a compound of Formula (I) ora pharmaceutically acceptable salt thereof given per day for a definednumber of days, can be ascertained by those skilled in the art usingconventional course of treatment determination tests.

The novel compounds of Formula (I) may also be used in association withthe veterinary treatment of mammals, other than humans, in need ofinhibition of CSBP/p38 or cytokine inhibition or production. Inparticular, CSBP/p38 mediated diseases for treatment, therapeutically orprophylactically, in animals include disease states such as those notedherein in the Methods of Treatment section, but in particular viralinfections. Examples of such viruses include, but are not limited to,lentivirus infections such as, equine infectious anaemia virus, caprinearthritis virus, visna virus, or maedi virus or retrovirus infections,such as but not limited to feline immunodeficiency virus (FIV), bovineimmunodeficiency virus, or canine immunodeficiency virus or otherretroviral infections.

The invention will now be described by reference to the followingbiological examples which are merely illustrative and are not to beconstrued as a limitation of the scope of the present invention.

BIOLOGICAL EXAMPLES

The cytokine-inhibiting effects of compounds of the present inventionmay be determined by the following in vitro assays:

Assays for Interleukin-1 (IL-1), Interleukin-8 (IL-8), and TumourNecrosis Factor (TNF) are well known in the art, and may be found in anumber of publications, and patents. Representative suitable assays foruse herein are described in Adams et al., U.S. Pat. No. 5,593,992, whosedisclosure is incorporated by reference in its entirety.

Interleukin-1 (IL-1)

Human peripheral blood monocytes are isolated and purified from eitherfresh blood preparations from volunteer donors, or from blood bank buffycoats, according to the procedure of Colotta et al, J Immunol, 132, 936(1984). These monocytes (1×10⁶) are plated in 24-well plates at aconcentration of 1-2 million/ml per well. The cells are allowed toadhere for 2 hours, after which time non-adherent cells are removed bygentle washing. Test compounds are then added to the cells for 1 hbefore the addition of lipopolysaccharide (50 ng/ml), and the culturesare incubated at 37° C. for an additional 24 h. At the end of thisperiod, culture supernatants are removed and clarified of cells and alldebris. Culture supernatants are then immediately assayed for IL-1biological activity, either by the method of Simon et al., J. Immunol.Methods, 84, 85, (1985) (based on ability of IL-1 to stimulate aInterleukin 2 producing cell line (EL-4) to secrete IL -2, in concertwith A23187 ionophore) or the method of Lee et al., J. Immuno Therapy, 6(1), 1-12 (1990) (ELISA assay).

In vivo TNF assay:

(1) Griswold et al., Drugs Under Exp. and Clinical Res., XIX (6),243-248 (1993); or

(2) Boehm, et al., Journal Of Medicinal Chemistry 39, 3929-3937 (1996)whose disclosures are incorporated by reference herein in theirentirety.

LPS-induced TNFα Production in Mice and Rats

In order to evaluate in vivo inhibition of LPS-induced TNFα productionin rodents, both mice and rats are injected with LPS.

Mouse Method

Male Balb/c mice from Charles River Laboratories are pretreated (30 min)with compound or vehicle. After the 30 min. pretreat time, the mice aregiven LPS (lipopolysaccharide from Esherichia coli Serotype 055-85,Sigma Chemical Co., St Louis, Mo.) 25 ug/mouse in 25 ul phosphatebuffered saline (pH 7.0) intraperitoneally. Two hours later the mice arekilled by CO₂ inhalation and blood samples are collected byexsanguination into heparinized blood collection tubes and stored onice. The blood samples are centrifuged and the plasma collected andstored at −20° C. until assayed for TNFα by ELISA.

Rat Method

Male Lewis rats from Charles River Laboratories are pretreated atvarious times with compound or vehicle. After a determined pretreattime, the rats are given LPS (lipopolysaccharide from Esherichia coliSerotype 055-85, Sigma Chemical Co., St Louis, Mo.) 3.0 mg/kgintraperitoneally. The rats are killed by CO₂ inhalation and heparinizedwhole blood is collected from each rat by cardiac puncture 90 min afterthe LPS injection. The blood samples are centrifuged and the plasmacollected for analysis by ELISA for TNFα levels.

ELISA Method

TNFα levels were measured using a sandwich ELISA, as described inOlivera et al., Circ. Shock, 37, 301-306, (1992), whose disclosure isincorporated by reference in its entirety herein, using a hamstermonoclonal antimurine TNFα (Genzyme, Boston, Mass.) as the captureantibody and a polyclonal rabbit antimurine TNFα (Genzyme) as the secondantibody. For detection, a peroxidase-conjugated goat antirabbitantibody (Pierce, Rockford, Ill.) was added, followed by a substrate forperoxidase (1 mg/ml orthophenylenediamine with 1% urea peroxide). TNFαlevels in the plasma samples from each animal were calculated from astandard curve generated with recombinant murine TNFα (Genzyme).

LPS-Stimulated Cytokine Production in Human Whole Blood

Assay: Test compound concentrations were prepared at 10× concentrationsand LPS prepared at 1 ug/ml (final conc. of 50 ng/ml LPS) and added in50 uL volumes to 1.5 mL eppendorf tubes. Heparinized human whole bloodwas obtained from healthy volunteers and was dispensed into eppendorftubes containing compounds and LPS in 0.4 mL volumes and the tubesincubated at 37 C. Following a 4 hour incubation, the tubes werecentrifuged at 5000 rpm for 5 min in a TOMY microfuge, plasma waswithdrawn and frozen at −80 C.Cytokine measurement: IL-1 and/or TNF were quantified using astandardized ELISA technology. An in-house ELISA kit was used to detecthuman IL-1 and TNF. Concentrations of IL-1 or TNF were determined fromstandard curves of the appropriate cytokine and IC50 values for testcompound (concentration that inhibited 50% of LPS-stimulated cytokineproduction) were calculated by linear regression analysis.CSBP/p38 Kinase Assay:

This assay measures the CSBP/p38-catalyzed transfer of ³²P from[a-³²P]ATP to threonine residue in an epidermal growth factor receptor(EGFR)-derived peptide (T669) with the following sequence:KRELVEPLTPSGEAPNQALLR(SEQ ID 1) (residues 661-681). (See Gallagher etal., “Regulation of Stress Induced Cytokine Production by PyridinylImidazoles: Inhibition of CSBP Kinase”, BioOrganic & MedicinalChemistry, 1997, 5, 49-64).

Reactions were carried in round bottom 96 well plate (from Corning) in a30 ml volume. Reactions contained (in final concentration): 25 mM Hepes,pH 7.5; 8 mM MgCl₂; 0.17 mM ATP (the KM_([ATP]) of p38 (see Lee et al.,Nature 300, n72 pg. 639-746 (December 1994)); 2.5 uCi of [g-32P]ATP; 0.2mM sodium orthovanadate; 1 mM DTT; 0.1% BSA; 10% glycerol; 0.67 mM T669peptide; and 2-4 nM of yeast-expressed, activated and purified p38.Reactions were initiated by the addition of [gamma-32P]Mg/ATP, andincubated for 25 min. at 37° C. Inhibitors (dissolved in DMSO) wereincubated with the reaction mixture on ice for 30 min prior to addingthe 32P-ATP. Final DMSO concentration was 0.16%. Reactions wereterminated by adding 10 ul of 0.3 M phosphoric acid, and phosphorylatedpeptide was isolated from the reactions by capturing it on p81phosphocellulose filters. Filters were washed with 75 mM phosphoricacids, and incorporated 32P was quantified using beta scintillationcounter. Under these conditions, the specific activity of p38 was400-450 pmol/pmol enzyme, and the activity was linear for up to 2 hoursof incubation. The kinase activity values were obtained aftersubtracting values generated in the absence of substrate which were10-15% of total values.

Representative compounds of Formula (I), Examples 1 to 167 havedemonstrated positive inhibitory activity in this assay, all having ofIC_(50's) of <100 uM in this binding assay.

TNF-α in Traumatic Brain Injury Assay

This assay provides for examination of the expression of tumor necrosisfactor mRNA in specific brain regions which follow experimentallyinduced lateral fluid-percussion traumatic brain injury (TBI) in rats.Since TNF-α is able to induce nerve growth factor (NGF) and stimulatethe release of other cytokines from activated astrocytes, thispost-traumatic alteration in gene expression of TNF-α plays an importantrole in both the acute and regenerative response to CNS trauma. Asuitable assay may be found in WO 97/35856 whose disclosure isincorporated herein by reference.

CNS Injury Model for IL-b mRNA

This assay characterizes the regional expression of interleukin-1β(IL-1β) mRNA in specific brain regions following experimental lateralfluid-percussion traumatic brain injury (TBI) in rats. Results fromthese assays indicate that following TBI, the temporal expression ofIL-1β mRNA is regionally stimulated in specific brain regions. Theseregional changes in cytokines, such as IL-1β play a role in the post-traumatic pathologic or regenerative sequalae of brain injury. Asuitable assay may be found in WO 97/35856 whose disclosure isincorporated herein by reference.

Angiogenesis Assay

Described in WO 97/32583, whose disclosure is incorporated herein byreference, is an assay for determination of inflammatory angiogenesiswhich may be used to show that cytokine inhibition will stop the tissuedestruction of excessive or inappropriate proliferation of bloodvessels.

Cigarette Smoke Exposure Model

A murine model of cigarette smoke inhalation was developed to explore arelationship to leukocyte trafficking and lung chemokine and cytokineproduction. Balb/c mice are exposed to smoke generated from commercialunfiltered cigarettes for a specified period of time and samples areobtained at varying times during the post-exposure. This model isdemonstrated in greater detail as shown below, in contrast to othersmoke extract models known in the art.

A model of cigarette smoke exposure in the mouse is established in whichmice are placed 6 at a time into a small animal plexiglass dosingchamber attached to a peristaltic pump whose intake is connected to aholder for a commercial unfiltered cigarette (Lucky Strike™). Along withfresh air, smoke is delivered into the chamber until the cigarette isconsumed (approximately 5 minutes). Varying numbers of cigarettes (2-4per day, 2-3 hr apart) are utilized for 1-3 consecutive days. Animalsare euthanized by pentobarbital overdose approximately 18 hours afterthe final exposure. Bronchoalveolar lavage with phosphate-bufferedsaline is performed for inflammatory cell enumeration, and BAL aliquotsand lungs are frozen for cytokine analysis. Smoke exposure results intime- and cigarette number-related increases in airway neutrophils, andlung chemokine (KC) and cytokine (IL-6) content.

To evaluate the role of a p38 MAP kinase inhibitor in this inflammatoryresponse, mice are treated with a p38 kinase inhibitor, a compound ofFormula (I) at approximately a 30 mg/kg, p.o. b.i.d. Reduction in lungKC (a murine homologue of IL-8) levels are assessed 1 day after exposure(prior to neutrophilia), and attenuated airway neutrophilia and lungIL-6 levels are assessed following 3 days of cigarette exposure.

Hypertussive Cough Models

Described below is an example of how to determine the usefulness of p38inhibitors in the treatment of hypertussive disorders or inflammationenhanced cough.

The directed antitussive activity of the compound in question if firstassessed, by a 10 to 30 minute pretreatment period by intraperitonealinjection or a 1 hour pretreatment period for oral administration. Theanimals (guinea pigs) are then subjected to an inhaled citricacid-induced cough challenge. The Citric Acid Induced Cough Model isshown in FIG. 2.

The effects of the compound are then assessed on the hypertussiveresponse that occurs 72 hours post aerosol exposure to antigen or LTD4exposure. Treatment of the animals occurs with the drug prior and/orafter antigen or LTD4 challenge, but not on the day of citric acidchallenge. The antigen or LTD4 induced hypertussive model is shown inFIG. 3.

The effects of known antitussive agents, dextromethorphan and codeine onCitric Acid Induced Cough in Guinea Pigs is shown in FIG. 4.

Inhalation of citric acid (CA; 0.4% for 1 minute) induces 11 to 15coughs during the exposure and 12-minute monitoring period in consciousguinea pigs. Exposure of sensitized animals to inhaled ovalbuminresulted in a hypertussive state (50-80% increase in CA-induced coughincidence) for several days, which positively correlated with airwayeosinophilia determined by bronchioalveolar lavage.

Similarly, inhalation of LTD4 (10 ug/ml for 1 minute) increases coughincidence and airway eosinophils 72 hours after exposure. Furtherexplanation and details may be found in PCT/US00/25386, filed 15 Sep.2000 whose disclosure is incorporated by reference in its entirety.

SYNTHETIC EXAMPLES

The invention will now be described by reference to the followingexamples which are merely illustrative and are not to be construed as alimitation of the scope of the present invention. All temperatures aregiven in degrees centigrade, all solvents are highest available purityand all reactions run under anhydrous conditions in an argon atmospherewhere necessary.

Mass spectra were run on an open access LC-MS system using electrosprayionization. LC conditions: 4.5% to 90% CH₃CN (0.02% TFA) in 3.2 min witha 0.4 min hold and 1.4 min re-equilibration; detection by MS, UV at 214,and a light scattering detector (ELS). Column: 1×40 mm Aquasil (C18)¹H-NMR (hereinafter “NMR”) spectra were recorded at 400 MHz using aBruker AM 400 spectrometer or a Bruker AVANCE 400. Multiplicitiesindicated are: s=singlet, d=doublet, t=triplet, q=quartet, m=multipletand br indicates a broad signal. Preparative (prep) hplc; ca 50 mg ofthe final products were injected in 500 uL of DMSO onto a 50×20 mm I. D.YMC CombiPrep ODS-A column at 20 mL/min with a 10 min gradient from 10%CH₃CN (0.1% TFA) to 90% CH₃CN (0.1% TFA) in H₂O (0.1% TFA) and a 2 minhold. Flash chromatography is run over Merck Silica gel 60 (230-400mesh).

Accepted abbreviations are used as described in the ACS Style Guide (TheACS Style Guide. A Manual for Authors; Dodd, J. A., Ed.; AmericanChemical Society: Washington, D.C., 1986; pp 47-69.). In addition thefollowing are used:

BOC t-butoxycarbonyl

eq indicates the proportion of molar equivalents of a reagent relativeto the principal reagent

NMP 1-methyl-2-pyrrolidinone

satd saturated

Rt hplc retention time

Example 1 Preparation of 1,5-diphenyl-7-methylsulfanyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one a)4-Chloro-2-methylsulfanyl-6-phenylamino-pyrimidine-5-carbonitrile

4,6-Dichloro-2-methylsulfanyl-pyrimidine-5-carbonitrile [Santilli, etal., J. Heterocycl. Chem. 1971, 8, 445-453] (0.222 grams (hereinafter“g”), 1.0 millimoles (hereinafter “mmol”)) in EtOH (2 milliliters(hereinafter “mL”)) and Et₂O (1 mL) was treated with aniline (184microliter (hereinafter “uL”), 2.0 mmol) in EtOH (1 mL). A clearsolution formed initially but rapidly formed a heavy precipitate. Themixture was stirred 30 minutes (hereinafter “min”) and was filtered, andthe solid was washed with 1:1 Et₂O, EtOH and then Et₂O, dried to afford162 miligrams (hereinafter “mg”) (59%) of the title compound as a whitesolid. LC MS m/e=277 (MH+), Rt=2.32 min.

b) 2-Methylsulfanyl-4-phenyl-6-phenylamino-pyrimidine-5-carbonitrile

The product of the previous example, (162 mg, 0.59 mmol), phenylboronicacid (360 mg, 2.95 mmol), Na₂CO₃ (318 mg, 3 mmol), dioxane (3 mL) andH₂O (1.5 mL) were combined and argon was bubbled through the mixture for30 min Pd[P(Ph)₃] (15 mg, 0.013 mmol) was added and the mixture washeated to 85° for 1.5 h, then cooled, diluted with H₂O (25 mL) andextracted with EtOAc (6×50 mL). The combined extracts were washed withH₂O, dried (Na₂SO₄), concentrated and filtered through a 10 g plug ofsilica (Varien Bond Elute®) with CH₂Cl₂ to afford the title compound asa white solid 185 mg (97%). LC MS m/e=319 (MH+), Rt=2.59 min.

c) (5-Aminomethyl-2-methylsulfanyl-6-phenyl-pyrimidin-4-yl) -phenylamine

The product of the previous example (151 mg, 0.47 mmol) was dissolved inwarm dioxane (6 mL), cooled to 23° and 1M LAH in Et₂O (1 mL, 1 mmol) wasadded and the resulting solution was heated to 55° for 1.5 h., dilutedwith EtOAc (10 mL) and then poured into 10% aq NaOH (20 mL) andextracted with more EtOAc (2×50 mL). The combined EtOAc was washed withH₂O, then satd aq NaCl, dried (Na₂SO₄) and concentrated to afford thetitle compound as a yellow solid. 153 mg (100%). LC MS m/e=323 (MH+),Rt=1.49 min

d)1,5-diphenyl-7-methylsulfanyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one

The product of the previous example (153 mg, 0.47 mmol) was dissolved intoluene (5 mL) and pyridine (2 mL). A 20% solution of COCl₂ in toluene(2 mL) was added and the resulting mixture was stirred 30 min, dilutedwith EtOAc (125 mL) and washed with 10% aq NaOH (20 mL) and H₂O (5×20mL) and concentrated. The crude product was purified by chromatotronchromatography (0-2% MeOH in CH₂Cl₂) and then the resulting nearly pureyellow solid was further purified by prep hplc. The resulting white foamwas dried in vacuo, triturated with H₂O, and filtered and dried in vacuoto afford 33 mg of the title compound as a white powder. LC MS m/e=349(MH+), Rt=2.12 min.

Example 21-(2,6-difluorophenyl)-5-(4-fluoro-2-methylphenyl)-7-methylsulfanyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-onea) 4-Chloro-6-(2,6-difluoro-phenylamino)-2-methylsulfanyl-pyrimidine-5-carbonitrile

2,6-di-Fluoroaniline (2.66 mL, 24 mmol), DMSO (12 mL) and NaH (0.912 g,22.8 mmol) were combined at 23°. When the foaming ceased4,6-Dichloro-2-methylsulfanyl-pyrimidine-5-carbonitrile [Santilli, etal., J. Heterocycl. Chem. 1971, 8, 445-453] (5.0 g, 22.82 mmol) wasadded in DMSO (12 mL). The reaction exothermed and the temperature wasmoderated with cold H₂O bath, then stirred at 23° for 3 h. The reactionwas diluted with EtOAc (300 mL) and washed with H₂O (4×) and satd aqNaCl (1×). Dried (Na₂SO₄) and concentrated to afford 6.21 g (82%) of atan foam. LC MS m/z=313 (MH⁺), Rt=2.37 min.

b)4-(2,6-Difluorophenylamino)-6-(4-fluoro-2-methylphenyl)-2-methylsulfanylpyrimidine-5-carbonitrile

The product of the previous example (4.0 g, 12.8 mmol),2-methyl-4-fluorophenylboronic acid (Lancaster) (5.91 g, 38.4 mmol),Na₂CO₃ (4.04 g, 38.4 mmol), dioxane (100 mL) and H₂O (50 mL) werecombined and a stream of argon was passed through the mixture for 15min. Pd[P(Ph)₃]₄ (Aldrich) (400 mg) was added and the mixture was heatedto 85° for 6 h. EtOAc (600 mL) was added and the organic phase waswashed with H₂O (100 mL). The aq wash was extracted with EtOAc (2×75 mL)and the combined organic phases were washed with more H₂O (50 mL) andsatd aq NaCl (50 mL), dried (Na₂SO₄), concentrated and the residue wasflash chromatographed with CH₂Cl₂. The desired fractions were pooled andconcentrated in vacuo to afford 4.16 g (84%) of a tan foam. LC MSm/z=387 (MH⁺), Rt=2.52 min

c)5-Aminomethyl-6-(4-fluoro-2-methylphenyl)-2-methylsulfanylpyrimidin-4-yl]-(2,6-difluorophenyl)amine

The product of the previous example (4.24 g, 11.0 mmol) was dissolved inEt₂O (200 mL) and 1M LAH in Et₂O (22 mL) was added dropwise. Afteraddition the mixture was heated to Et₂O reflux for 1.5 h, cooled to 4°and quenched by the addition of H₂O (1.1 mL), then 10% aq NaOH (5.5 mL)and then more H₂O (5.5 mL), stirred 10 min then 2.5% CH₃OH in CH₂Cl₂(400 mL) was added. Stirred 15 min and the organic layer was decantedand the residue was washed with additional 2.5% methanolic CH₂Cl₂ (200mL). The combined organic layers were dried (Na₂SO₂) and concentrated toafford 4.02 g (94%) of a yellow foamy solid. LC MS m/z=391 (MH⁺),Rt=1.62 min.

d)1-(2,6-difluorophenyl)-5-(4-fluoro-2-methylphenyl)-7-methylsulfanyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one

The product of the previous example, (4.02 g, 10.4 mmol) was dissolvedin THF (100 mL) and carbonyldiimidazole (2.23 g, 13.8 mmol) was added.The resulting mixture was stirred 16 h, diluted with EtOAc (1 L) andwashed with H₂O (4×150 mL) and satd aq NaCl (150 mL), dried (Na₂SO₄) andconcentrated to a brown foam. The residue was dissolved in CH₂Cl₂ andflash chromatographed in 0-2% CH₃OH in CH₂Cl₂ to afford 2.97 g (69%) ofthe title compound as an off white solid. LC MS m/z=417 (MH⁺), Rt=2.27min.

Example 31-(2,6-difluorophenyl)-5-(4-fluoro-2-methylphenyl)-7-methylsulfonyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one

The product of the preceeding example, example 2 (2.14 g, 5.14 mmol),CH₂Cl₂ (100 mL) and meta-chloroperoxybenzoic acid (57-85%) (3.102 g,10.26 mmol if 57%) were dissolved together. After 16 h, the reaction wasdiluted with EtOAc (300 mL) and washed with 5% aq Na₂CO₃ (6×50 mL), H₂O(50 mL) and satd aq NaCl (50 mL), dried Na₂SO₂ and concentrated toafford 2.3 g (100%) of the title compound as a white solid. LC MSm/z=417 (MH⁺), Rt=1.94 min

Example 41-(2,6-difluorophenyl)-5-(4-fluoro-2-methylphenyl)-7-(piperidin-4-ylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-onetrifluoroacetate a)1-(2,6-difluorophenyl)-5-(4-fluoro-2-methylphenyl)-7-(1-tert-butoxycarbonyl-piperidin-4-ylamino)-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2-one

The product of the previous example, Example 3 (90 mg, 0.2 mmol), NMP (1mL) and 4-amino-1-BOC-piperidine (Astatech) (200 mg, 1.0 mmol) wereheated in an oil bath at 650 for 16 h. The reaction was cooled to 23°,diluted with EtOAc (75 mL) and washed with 10% aq citric acid (2×), H₂Oand satd aq NaCL, dried (Na₂SO₄), and concentrated to afford 112 mg of awhite solid. LC MS m/z=569 (MH⁺), Rt=2.14 min

b)1-(2,6-difluorophenyl)-5-(4-fluoro-2-methylphenyl)-7-(piperidin-4-ylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-onetrifluoroacetate

The product of the preceding example was dissolved in TFA (5 mL) andallowed to stand for 15 min, then concentrated and purified by prep hplcto afford 56.8 mg (61%) of a white powder. LC MS m/z=469 (MH⁺), Rt=1.35min

Example 51-(2,6-difluorophenyl)-5-(4-fluoro-2-methylphenyl)-7-(2-dimethylaminoethylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-onetrifluoroacetate

The product of example 3 (90 mg, 0.2 mmol) was dissolved in NMP (1 mL)and dimethylaminoethylamine (110 uL, 1.0 mmol) was added and theresulting brown soln was stirred on an oil bath heated to 65° for 16 h.,diluted with EtOAc (75 mL) and washed with H₂O (3×) and satd aq NaCl,dried (Na₂SO₄) concentrated and purified by prep hplc to afford 68 mg(75%). LC MS m/z=457 (MH⁺), Rt=1.39 min

Example 61-(2,6-difluorophenyl)-5-(4-fluoro-2-methylphenyl)-7-(1,3-dihydroxyprop-2-ylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one

The product of example 3 (90 mg, 0.2 mmol) was dissolved in NMP (1 mL)and serinol (91 mg, 1.0 mmol) was added. The solution was heated to 65°for 48 h, diluted with EtOAc (75 mL) and washed with 10% aq citric acid(2×), H₂O, and satd aq NaCl, dried (Na₂SO₄), concentrated and purifiedby prep hplc to afford 46 mg (50%). LC MS m/z=460 (MH⁺), Rt=1.37 min

The compounds in Table 1 were prepared by either the method of Example 5(method A) or by the method of Example 6 (method B), using theappropriate amine. Note that Methods A and B differ by the absence(method A) or presence (method B) of an aqueous citric acid wash duringwork-up. For those examples where the reaction time and/or temperaturewas varied from those given in Examples 5 and 6, the changes areindicated in Table 1, below.

TABLE 1 Method LC MS Example Compound name (variations) m/z Rt min 71-(2,6-difluorophenyl)-5-(4-fluoro-2- A 469 1.49methylphenyl)-7-(1-methylpiperazin-4-yl)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one trifluoroacetate 81-(2,6-difluorophenyl)-5-(4-fluoro-2- A 437 1.64methylphenyl)-7-(imidazol-1yl-)-3,4-dihydro- (5 h)1H-pyrimido[4,5-d]pyrimidin-2-one trifluoroacetate 91-(2,6-difluorophenyl)-5-(4-fluoro-2- B 444 1.65methylphenyl)-7-([2-hydroxyethyl)- (2 h)methylamino]-3,4-dihydro-1H-pyrimido[4,5-d]- pyrimidin-2-one 101-(2,6-Difluorophenyl)-5-(4-fluoro-2- B 470 1.79methylphenyl)-7-(4-hydroxypiperdin-1-yl)-3,4- (4 h)dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one 111-(2,6-difluorophenyl)-5-(4-fluoro-2- B 526 2.42methylphenyl)-7-(4-carboethoxypiperidin-1-yl)- (1 h)3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one 121-(2,6-Difluorophenyl)-5-(4-fluoro-2- B 484 2.49methylphenyl)-7-(4-hydroxymethylpiperdin-1- (1 h)yl)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2- one 131-(2,6-difluorophenyl)-5-(4-fluoro-2- B 474 1.55methylphenyl)-7-di(ethan-2-ol-)amino-3,4- (24 H)dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one 141-(2,6-difluorophenyl)-5-(4-fluoro-2- A 483 1.37methylphenyl)-7-(1-methylpiperidin-4-yl-amino)-3,4-dihydro-1H-pyrimido[4,5- d]pyrimidin-2-one trifluoroacetate15 1-(2,6-difluorophenyl)-5-(4-fluoro-2- B 456 2.12methylphenyl)-7-(1-morpholin-4-yl)-3,4- (16 h)dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one 161-(2,6-difluorophenyl)-5-(4-fluoro-2- A 499 1.40methylphenyl)-7-(2-morpholin-4-yl ethylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one trifluoroacetate 171-(2,6-difluorophenyl)-5-(4-fluoro-2- A 483 1.50methylphenyl)-7-(2-pyrrolidin-1-yl ethylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one trifluoroacetate 181-(2,6-difluorophenyl)-5-(4-fluoro-2- A 497 1.55methylphenyl)-7-(2-piperidin-1-yl ethylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one trifluoroacetate 191-(2,6-difluorophenyl)-5-(4-fluoro-2- A 491 1.47methylphenyl)-7-(2-pyridin-3-yl ethylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one trifluoroacetate 201-(2,6-difluorophenyl)-5-(4-fluoro-2- A 485 1.55methylphenyl)-7-(2-diethylamino ethylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one trifluoroacetate 211-(2,6-difluorophenyl)-5-(4-fluoro-2- A 491 1.47methylphenyl)-7-(2-pyridin-3-yl ethylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one trifluoroacetate 221-(2,6-difluorophenyl)-5-(4-fluoro-2- A¹ 414 1.97methylphenyl)-7-(2-dimethylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one trifluoroacetate 231-(2,6-difluorophenyl)-5-(4-fluoro-2- A² 400 1.64methylphenyl)-7-(2-methylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one trifluoroacetate 241-(2,6-difluorophenyl)-5-(4-fluoro-2- B 474 1.45methylphenyl)-7-(2-methyl-1,3-dihydroxyprop- (80°,2-ylamino)-3,4-dihydro-1H- 24 h) pyrimido[4,5d]pyrimidin-2-one 251-(2,6-difluorophenyl)-5-(4-fluoro-2- B 444 1.55methylphenyl)-7-((R)-2-hydroxy-1-methyl- (2 h)ethylamino)-3,4-dihydro-1H-pyrimido[4,5- d]pyrimidin-2-one 261-(2,6-difluorophenyl)-5-(4-fluoro-2- B 444 1.55methylphenyl)-7-((S)-2-hydroxy-1-methyl- (2 h)ethylamino)-3,4-dihydro-1H-pyrimido[4,5- d]pyrimidin-2-one 271-(2,6-difluorophenyl)-5-(4-fluoro-2- B 458 1.57methylphenyl)-7-(2-hydroxy-1,1-dimethyl- (80°,ethylamino)-3,4-dihydro-1H-pyrimido[4,5- 4 h) d]pyrimidin-2-one 281-(2,6-difluorophenyl)-5-(4-fluoro-2- B 490 1.19methylphenyl)-7-(2-hydroxy-1,1-bis- (85°,hydroxymethyl-ethylamino)-3,4-dihydro-1H- 16 h)pyrimido[4,5-d]pyrimidin-2-one 29 1-(2,6-difluorophenyl)-5-(4-fluoro-2-B 430 1.50 methylphenyl)-7-(2-hydroxyethylamino)-3,4- (0.5 h)dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one 301-(2,6-difluorophenyl)-5-(4-fluoro-2- B 460 1.32methylphenyl)-7-(2,3-dihydroxypropylamino)- (16 h)3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one ¹Using 40% aqdimethylamine. ²Using 2M methylamine in THF.

Example 311-(26-difluorophenyl)-5-(4-fluoro-2-methylphenyl)-7-methylsulfinyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one

The product of example 2 (204 mg, 0.49 mmol) in THF was treated dropwisewith Oxone® (0.307 g, 0.5 mmol) in H₂O (10 mL). The mixture was stirredat 23° for 2 h, diluted with EtOAc (100 mL) and washed with H₂O (2×25mL) and satd aq NaCl (25 mL), dried (Na₂SO₄), and concentrated. Theresidue was purified by prep hplc to afford the sulfoxide as a whitepowder. LC MS m/z=433 (MH⁺), Rt=1.70 min

Example 321-(2,6-difluorophenyl)-5-(4-fluoro-2-methylphenyl)-7-(1-methyl-1H-imidazol-2-yl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-onetrifluoroacetate

N-Methylimidazole (82 uL, 1.0 mmol) in dry THF was cooled to −70° andn-butyl lithium (2.5 M in hexane) (0.36 mL, 0.9 mmol) was added, themixture was stirred 15 min and then the product of example 3 (45 mg, 0.1mmol) was added and the reaction was warmed to 23°, and stirred 30 min.The reaction was poured into satd aq NaHCO₃ (20 mL) and stirred 5 minand then extracted with EtOAc (2×). The combined EtOAc was washed withH₂O (3×), satd aq NaCl, dried (Na₂SO₄) and concentrated. The residue waspurified by prep hplc to afford 11.6 mg (26%) of the title compound as awhite powder. LC MS m/z=451 (MH⁺), Rt=1.55 min.

Example 331-(2,6-difluorophenyl)-5-(4-fluoro-2-methylphenyl)-7-(1-piperazin-4-yl)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one

The title compound was prepared by the method of example 4 except that1-BOC-piperazine (Fluka) was the amine. TFA deblocking of theintermediate BOC protected compound as in example 4 and prep hplcafforded the title compound as a white powder. LC MS m/z=455 (MH⁺),Rt=1.55 min.

Example 341-(2,6-difluorophenyl)-5-(4-fluoro-2-methylphenyl)-7-(4-carboxypiperidin-1-yl)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one

The product of example 11 (56 mg, 0.11 mmol) was dissolved in THF (2 mL)and LiOH (24 mg, 1.0 mmol) in H₂O (1.0 mL) was added, and the resultingsoln was stirred for 4 h. The reaction was concentrated and redissolvedin DMSO and purified by prep hplc to afford 24.8 mg (45%) of the titlecompound. LC MS m/z=498 (MH⁺), Rt=1.64 min.

The sulfides in examples 35 to 37 (Table 2) were prepared by the methodof Example 2, except that the boronic acid in step 2b was varied asdepicted in Table 2. below.

TABLE 2 LC MS Rt Example Compound name Boronic acid m/z (min) 351-(2,6-Difluorophenyl)-5-phenyl-7- methyl-sulfanyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one

385 2.19 36 1-(2,6-Difluorophenyl)-5-(4-fluorophenyl)-7-methylsulfanyl-3,4- dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one

403 2.19 37 1-(2,6-difluorophenyl)-5-(2-methylphenyl)-7-methylsulfanyl-3,4- dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one

399 2.20

The sulfides in examples 38-44 (Table 3) were prepared by the method ofExample 2 except that the amine in step 2a was varied as depicted inTable 3, below.

TABLE 3 LC MS Example Compound Name Amine m/z Rt (min) 381-((R)-1-Phenylethyl-5-(2-methyl-4- R-α-methyl- 409 2.39fluoro)phenyl-7-methylsulfanyl-3,4- benzylaminedihydro-1H-pyrimido[4,5-d]pyrimidin- 2-one 391-((S)-1-Phenylethyl-5-(2-methyl-4- S-α-methyl- 409 2.39fluoro)phenyl-7-methylsulfanyl-3,4- benzylaminedihydro-1H-pyrimido[4,5-d]pyrimidin- 2-one 401-(2-Chlorophenyl)-5-(2-methyl-4- 2-chloroaniline 415 2.17fluoro)phenyl-7-methylsulfanyl-3,4- dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one 41 1-Cyclohexyl-5-(2-methyl-4- cyclohexyl- 387 2.62fluoro)phenyl-7-methylsulfanyl-3,4- aminedihydro-1H-pyrimido[4,5-d]pyrimidin- 2-one 421-(2-Methylphenyl)-5-(2-methyl-4- 2- 395 2.20fluoro)phenyl-7-methylsulfanyl-3,4- methylanilinedihydro-1H-pyrimido[4,5-d]pyrimidin- 2-one 431-(2,6-Dimethylphenyl)-5-(2-methyl- 2,6-di- 409 2.224-fluoro)phenyl-7-methylsulfanyl-3,4- methylaniline dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one 44 1-(2-Fluorophenyl)-5-(2-methyl-4-2-fluoroaniline 399 2.10 fluoro)phenyl-7-methylsulfanyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin- 2-one

The sulfones in Table 4 were made by the procedure of Example 3 exceptthat the substrate sulfides were the products of the examples indicated.

TABLE 4 LC MS Example Compound name Method* m/z Rt (min) 451-(2,6-Difluorophenyl)-5-phenyl-7- 35 417 1.75methylsulfonyl-3,4-dihydro-1H- pyrimido[4,5-d]pyrimidin-2-one 461-(2,6-Difluorophenyl)-5-(4- 36 436 1.82fluorophenyl)-7-methylsulfonyl-3,4- dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one 47 1-(2,6-Difluorophenyl)-5-(2-methylphenyl)- 37 4311.87 7-methylsulfonyl-3,4-dihydro-1H- pyrimido[4,5-d]pyrimidin-2-one 481-((R))-1-Phenylethyl)-5-(2-methyl-4- 38 441 2.01fluoro)phenyl-7-methylsulfonyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one 491-((S)-1-Phenylethyl)-5-(2-methyl-4- 39 441 2.01fluoro)phenyl-7-methylsulfonyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one 50 1-(2-Chlorophenyl)-5-(2-methyl-4-40 447 1.94 fluoro)phenyl-7-methylsulfonyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one 511-Cyclohexyl-5-(2-methyl-4-fluoro)phenyl- 41 419 2.027-methylsulfonyl-3,4-dihydro-1H- pyrimido[4,5-d]pyrimidin-2-one 521-(2-Methylphenyl)-5-(2-methyl-4- 42 427 1.82fluoro)phenyl-7-methylsulfonyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one 531-(2,6-Dimethylphenyl)-5-(2-methyl-4- 43 441 1.92fluoro)phenyl-7-methylsulfonyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one 54 1-(2-Fluorophenyl)-5-(2-methyl-4-44 431 1.84 fluoro)phenyl-7-methylsulfonyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one *the substrate is the product of thenoted example #

Example 551-(2,6-Difluorophenyl)-5-phenyl-7-(4-methylpiperazin-1-yl)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one

The product of example 45 (41.6 mg, 0.1 mmol), 4-methylpiperazine (30mg, 0.3 mmol) and NMP (1.0 mL) were dissolved together and heated to 65°for 18 h. The NMP was removed in high vacuum and the residue waspurified by prep hplc to afford 17 mg of the title compound. LC MSm/z=437 (MH⁺), Rt=1.47 min.

Example 561-(2,6-Difluorophenyl)-5-phenyl-7-piperazin-1-yl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one

The product of example 45 (41.6 mg, 0.1 mmol), and 1-BOC-piperazine(Fluka) were treated by the method of example 55, omitting the hplcstep, to afford the BOC protected intermediate. This product wasdeblocked by the procedure of example 4b and purified by prep hplc toafford the title compound. LC MS m/z=422 (MH⁺), Rt=1.37 min.

The compounds in Table 5 were prepared by either the method of Example5, using the appropriate amine and the sulfone shown in Table 5 (MethodC; includes aqueous work-up), or the method of Example 55 using theappropriate amine and the sulfone shown in Table 5 (Method D; withconcentration of the crude reaction mixture, then preparation hplc), orthe method of Example 33 using the appropriate sulfone (Method E; aq.work-up with citric acid, deblocking, and prep hplc) or the method ofExample 56 using the appropriate sulfone as shown in Table 5 (Method F;concentration, deblocking, and prep hplc). In the table, method* is thesubstrate is the sulfone of the noted example.

TABLE 5 LC MS Example Compound name Method* m/z Rt 571-(2,6-difluorophenyl)-5-(2-methylphenyl)-7-(2- C 467 1.44diethylaminoethylamino)-3,4-dihydro-1H- (47)pyrimido[4,5-d]pyrimidin-2-one trifluoroacetate 581-(2,6-difluorophenyl)-5-(2-methylphenyl)-7-(1- E 437 1.50piperazin-4-yl)-3,4-dihydro-1H-pyrimido[4,5- (47) d]pyrimidin-2-one 591-(2,6-diflurorophenyl)-5-phenyl-7-(2- D 412 1.60hydroxyethyl)methylamino-3,4-dihydro-1H- (45)pyrimido[4,5-d]pyrimidin-2-one 60 1-(2,6-diflurorophenyl)-5-phenyl-7-(4-D 494 1.85 carboethoxypiperidin-1-yl)-3,4-dihydro-1H- (45)pyrimido[4,5-d]pyrimidin-2-one 61 1-(2,6-diflurorophenyl)-5-phenyl-7-(4-D 438 1.74 hydroxypiperidin-1-yl)-3,4-dihydro-1H- (45)pyrimido[4,5-d]pyrimidin-2-one 621-(2,6-diflurorophenyl)-5-phenyl-7-(imidazol-1- D 405 1.47yl)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2- (45) one 631-(2,6-diflurorophenyl)-5-phenyl-7-(morpholin-1- D 424 2.04yl)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2- (45) one 641-(2,6-Difluorophenyl)-5-(4-fluorophenyl-7-(4- D 455 1.47methylpiperazin-1-yl)-3,4-dihydro-1H- (46)pyrimido[4,5-d]pyrimidin-2-one 651-(2,6-diflurorophenyl)-5-(4-fluorophenyl)-7-(2- D 430 1.72hydroxyethyl)methylamino-3,4-dihydro-1H- (46)pyrimido[4,5-d]pyrimidin-2-one 661-(2,6-difluorophenyl)-5-(4-fluorophenyl)-7- F 441 1.40(piperazin-1-yl)-3,4-dihydro-1H-pyrimido[4,5- (46) d]pyrimidin-2-one 671-(2,6-difluorophenyl)-5-(4-fluorophenyl)-7-(4- D 512 2.42carboethoxypiperidin-1-yl)-3,4-dihydro-1H- (46)pyrimido[4,5-d]pyrimidin-2-one 681-(2,6-difluorophenyl)-5-(4-fluorophenyl)-7-(4- D 456 1.95hydroxypiperidin-1-yl)-3,4-dihydro-1H- (46)pyrimido[4,5-d]pyrimidin-2-one 691-(2,6-diflurorophenyl)-5-(4-fluorophenyl)-7- D 423 1.52(imidazol-1-yl)-3,4-dihydro-1H-pyrimido[4,5- (46) d]pyrimidin-2-one 701-(2,6-diflurorophenyl)-5-(4-fluorophenyl)-7- D 442 2.10(morpholin-1-yl)-3,4-dihydro-1H-pyrimido[4,5- (46) d]pyrimidin-2-one 711-(2,6-diflurorophenyl)-5-(4-fluorophenyl)-7-(4- D 470 1.90hydroxymethylpiperidin-1-yl)-3,4-dihydro-1H- (46)pyrimido[4,5-d]pyrimidin-2-one

Example 72 1-(2,6-difluorophenyl)-5-phenyl-7-(1-methyl-1H-imidazol-2-yl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one trifluoroacetate

The product of example 45 was converted to the target compound by theprocedure of example 32. LC MS m/z=419 (MH⁺), Rt=1.42 min

Example 731-(2,6-difluorophenyl)-5-(4-fluorophenyl)-7-(1-methyl-1H-imidazol-2-y)l-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-onetrifluoroacetate

The product of example 46 was converted to the target compound by theprocedure of example 32. LC MS m/z=437, (MH⁺), Rt=1.44 min.

Example 741-(2,6-difluorophenyl)-5-phenyl-7-(4-carboxypiperidin-1-yl)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-onetrifluoroacetate

The product of example 60 was converted to the target compound by theprocedure of example 34. LC MS m/z=466 (MH+), Rt=2.39 min

Example 751-(2,6-difluorophenyl)-5-(4-fluorophenyl)-7-(4-carboxypiperidin-1-yl)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-onetrifluoroacetate

The product of example 67 was converted to the target compound by theprocedure of example 34. LC MS m/z=484 (MH+), Rt=1.95 min

Example 761-(2-Chlorophenyl)-5-(4-fluoro-2-methylphenyl)-7-(2-pyrrolidin-1-yl-ethylamino)-3,4-dihydro-1H-pyrimidido[4,5-d]pyrimidin-2-one

The product of example 50 (75 mg, 0.168 mmol), pyrollidin-1-ylethylamine (57 mg, 0.5 mmol) were combined in a sealed tube at 90° for20 h. Concentration and prep hplc afforded the title compound as anamber oil. LC MS m/z=480 (MH+), Rt=1.52 min

Example 771-(2-Chlorophenyl)-5-(4-fluoro-2-methylphenyl)-7-(1H-tetrazol-5-ylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-one

The method of example 76 was repeated except using 5-aminotetrazole asthe amine and the reaction was heated to 150° for 10 h. Concentrationand prep hplc afforded the title compound as an amber oil. LC MS m/z=450(MH+), Rt=1.94 min.

The compounds in Table 6 were prepared by either the method of Example76 (method G) or the method of Example 77 (method H) using theappropriate amine and the sulphone of the example indicated.

TABLE 6 LC MS Example Compound name Method* m/z Rt min 781-(2-Chlorophenyl)-5-(4-fluoro-2-methylphenyl)- (50) G 495 1.637-(2-piperidin-1-ylethylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-one 791-(2-Chlorophenyl)-5-(4-fluoro-2-methylphenyl)- (50) H 472 1.457-(2-hydroxy-1-hydroxymethyl-1-methylethylamino)-3,4-dihydro-1H-pyrimido[4,5- d]pyrimidin-one 801-(2-Chlorophenyl)-5-(4-fluoro-2-methylphenyl)- (50) G 442 1.627-((R)-2-hydroxy-1-methylethylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-one 811-(2-Chlorophenyl)-5-(4-fluoro-2-methylphenyl)- (50) G 442 1.607-((S)-2-hydroxy-1-methylethylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-one 821-(2-Chlorophenyl)-5-(4-fluoro-2-methylphenyl)- (50) H 488 1.317-(2-hydroxy-1,1-bis-hydroxymethyl-ethylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-one 831-(2-Chlorophenyl)-5-(4-fluoro-2-methylphenyl)- (50) H 447 2.267-(2-hydroxy-1,1-dimethyl-ethylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-one 841-(2-Chlorophenyl)-5-(4-fluoro-2-methylphenyl)- (50) G 442 1.757-[(2-hydroxyethy)-methylamino]-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-one 851-(2-Chlorophenyl)-5-(4-fluoro-2-methylphenyl)- (50) H 519 1.877-[(racemic)-3-exo-(bicyclo[2.2.1]hept-ene-2- carboxylic acidamide)amino])-3,4-dihydro-1H- pyrimido[4,5-d]pyrimidin-one 861-(2-Chlorophenyl)-5-(4-fluoro-2-methylphenyl)- (50) G 519 1.807-[(racemic)-3-endo-(bicyclo[2.2.1]hept-ene-2- carboxylic acidamide)amino]-3,4-dihydro-1H- pyrimido[4,5-d]pyrimidin-one 871-(2-Chlorophenyl)-5-(4-fluoro-2-methylphenyl)- (50) G 470 1.777-{([1,3]dioxolan-2-ylmethyl)-amino}-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-one 881-(2-Chlorophenyl)-5-(4-fluoro-2-methylphenyl)- (50) G 509 1.697-[3-(2-oxo-pyrrolidin-1-yl) propylamino]-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-one 891-(2-Chlorophenyl)-5-(4-fluoro-2-methylphenyl)- (50) G 427 1.537-(2-hydroxyethylamino)-3,4-dihydro-1H- pyrimido[4,5-d]pyrimidin-one 901-((S)-1-Phenylethyl)-5-(4-fluoro-2- (49) G 475 1.59methylphenyl)-7-(2-pyrrolidin-1-yl-ethylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-one 911-((S)-1-Phenylethyl)-5-(4-fluoro-2- (49) G 489 1.65methylphenyl)-7-(2-piperidin-1-yl ethylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-one 921-((S)-1-Phenylethyl)-5-(4-fluoro-2- (49) H 446 2.10methylphenyl)-7-(1H-tetrazol-5-ylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-one 931-((S)-1-Phenylethyl)-5-(4-fluoro-2- (49) G 436 1.69methylphenyl)-7-((R)-2-hydroxy-1-methyl-ethylamino)-3,4-dihydro-1H-pyrimido[4,5- d]pyrimidin-one 941-((S)-1-Phenylethyl)-5-(4-fluoro-2- (49) G 436 1.79methylphenyl)-7-[(2-hydroxyethyl)-methylamino]-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-one 951-((S)-1-Phenylethyl)-5-(4-fluoro-2- (49) G 464 1.85methylphenyl)-7-[([1,3]dioxolan-2-ylmethyl)amino]-3,4-dihydro-1H-pyrimido[4,5- d]pyrimidin-one 961-((S)-1-Phenylethyl)-5-(4-fluoro-2- (49) G 503 1.80methylphenyl)-7-[3-(2-oxo-pyrrolidin-1-yl)-propylamino]-3,4-dihydro-1H-pyrimido[4,5- d]pyrimidin-one 971-((S)-1-Phenylethyl)-5-(4-fluoro-2- (49) G 422 1.63methylphenyl)-7-(2-hydroxyethylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-one 981-((S)-1-Phenylethyl)-5-(4-fluoro-2- (49) G 489 1.47methylphenyl)-7-(3-pyrrolidin-1-ylpropylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-one 991-Cyclohexyl-5-(4-fluoro-2-methylphenyl)-7-(2- (51) G 453 1.55pyrrolidin-1-yl-ethylamino)-3,4-dihydro-1H- pyrimido[4,5-d]pyrimidin-one100 1-Cyclohexyl-5-(4-fluoro-2-methylphenyl)-7-(2- (51) G 467 1.72piperidin-1-yl ethylamino)-3,4-dihydro-1H- pyrimido[4,5-d]pyrimidin-one101 1-Cyclohexyl-5-(4-fluoro-2-methylphenyl)-7-(1H- (51) H 424 2.17tetrazol-5-ylamino)-3,4-dihydro-1H-pyrimido[4,5- d]pyrimidin-one 1021-Cyclohexyl-5-(4-fluoro-2-methylphenyl)-7-(2- (51) G 444 1.66hydroxy-1-hydroxymethyl-1-methylethylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-one 1031-Cyclohexyl-5-(4-fluoro-2-methylphenyl)-7-((R)- (51) G 414 1.682-hydroxy-1-methyl-ethylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-one 1041-Cyclohexyl-5-(4-fluoro-2-methylphenyl)-7-((S)- (51) G 428 2.062-hydroxy-1-methylethylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-one 1051-Cyclohexyl-5-(4-fluoro-2-methylphenyl)-7-(2- (51) H 460 1.52hydroxy-1,1-bis-hydroxymethyl-ethylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-one 1061-Cyclohexyl-5-(4-fluoro-2-methylphenyl)-7-(2- (51) G 428 1.85hydroxy-1,1-dimethyl-ethylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-one 1071-Cyclohexyl-5-(4-fluoro-2-methylphenyl)-7- (51) G 442 1.84[([1,3]dioxolan-2-ylmethyl)amino]-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-one 1081-Cyclohexyl-5-(4-fluoro-2-methylphenyl)-7-[3- (51) G 481 1.72(2-oxo-pyrrolidin-1-yl)-propylamino]-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-one 1091-Cyclohexyl-5-(4-fluoro-2-methylphenyl)-7-(2- (51) G 400 1.59hydroxyethylamino)-3,4-dihydro-1H-pyrimido[4,5- d]pyrimidin-one 1101-Cyclohexyl-5-(4-fluoro-2-methylphenyl)-7-(3- (51) G 467 1.47pyrrolidin-1-ylpropylamino)-3,4-dihydro-1H- pyrimido[4,5-d]pyrimidin-one111 1-(2-Methylphenyl)-5-(4-fluoro-2-methylphenyl)- (52) G 461 1.427-(2-pyrrolidin-1-yl-ethylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-one 1121-(2-Methylphenyl)-5-(4-fluoro-2-methylphenyl)- (52) G 475 1.497-(2-piperidin-1-yl ethylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-one 1131-(2-Methylphenyl)-5-(4-fluoro-2-methylphenyl)- (52) G 452 1.417-(2-hydroxy-1-hydroxymethyl-1-methyl-ethylamino)-3,4-dihydro-1H-pyrimido[4,5- d]pyrimidin-one 1141-(2-Methylphenyl)-5-(4-fluoro-2-methylphenyl)- (52) G 421 1.537-((R)-2-hydroxy-1-methyl-ethylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-one 1151-(2-Methylphenyl)-5-(4-fluoro-2-methylphenyl)- (52) G 422 1.547-((S)-2-hydroxy-1-methylethylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-one 1161-(2-Methylphenyl)-5-(4-fluoro-2-methylphenyl)- (52) H 468 1.307-(2-hydroxy-1,1-bis-hydroxymethyl-ethylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-one 117-(2-Methylphenyl)-5-(4-fluoro-2-methylphenyl)-7- (52) G 436 1.60(2-hydroxy-1,1-dimethyl-ethylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-one 1181-(2-Methylphenyl)-5-(4-fluoro-2-methylphenyl)- (52) G 422 1.667-[(2-hydroxyethyl)-methylamino]-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-one 1191-(2-Methylphenyl)-5-(4-fluoro-2-methylphenyl)- (52) G 450 1.707-[([1,3]dioxolan-2-ylmethyl)amino]-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-one 1201-(2-Methylphenyl)-5-(4-fluoro-2-methylphenyl)- (52) G 489 1.607-[3-(2-oxo-pyrrolidin-1-yl)-propylamino]-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-one 1211-(2-Methylphenyl)-5-(4-fluoro-2-methylphenyl)- (52) G 408 1.427-(2-hydroxyethylamino)-3,4-dihydro-1H- pyrimido[4,5-d]pyrimidin-one 1221-(2,6-Dimethylphenyl)-5-(4-fluoro-2- (53) G 475 1.48methylphenyl)-7-(2-pyrrolidin-1-yl-ethylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-one 1231-(2,6-Dimethylphenyl)-5-(4-fluoro-2- (53) G 489 1.55methylphenyl)-7-(2-piperidin-1-yl ethylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-one 1241-(2,6-Dimethylphenyl)-5-(4-fluoro-2- (53) H 446 1.95methylphenyl)-7-(1H-tetrazol-5-ylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-one 1251-(2,6-Dimthylphenyl)-5-(4-fluoro-2- (53) H 466 1.49methylphenyl)-7-(2-hydroxy-1-hydroxymethyl-1- methylethylamino)-3,4-dihydro-1H-pyrimido[4,5- d]pyrimidin-one 1261-(2,6-Dimethylphenyl)-5-(4-fluoro-2- (53) G 436 1.58methylphenyl)-7-((R)-2-hydroxy-1-methyl-ethylamino)-3,4-dihydro-1H-pyrimido[4,5- d]pyrimidin-one 1271-(2,6-Dimethylphenyl)-5-(4-fluoro-2- (53) G 436 1.60methylphenyl)-7-((S)-2-hydroxy-1-methylethylamino)-3,4-dihydro-1H-pyrimido[4,5- d]pyrimidin-one 1281-(2,6-Dimethylphenyl)-5-(4-fluoro-2- (53) H 482 1.36methylphenyl)-7-(2-hydroxy-1,1-bis-hydroxymethyl-ethylamino)-3,4-dihydro-1H- pyrimido[4,5-d]pyrimidin-one129 -(2,6-Dimethylphenyl)-5-(4-fluoro-2- (53) G 450 1.70methylphenyl)-7-(2-hydroxy-1,1-dimethyl-ethylamino)-3,4-dihydro-1H-pyrimido[4,5- d]pyrimidin-one 1301-(2,6-Dimethylphenyl)-5-(4-fluoro-2- (53) G 436 1.72methylphenyl)-7-[(2-hydroxyethyl)-methylamino]-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-one 1311-(2,6-Dimethylphenyl)-5-(4-fluoro-2- (53) G 464 1.77methylphenyl)-7-[([1,3]dioxolan-2-ylmethyl)amino]-3,4-dihydro-1H-pyrimido[4,5- d]pyrimidin-one 1321-(2,6-Dimethylphenyl)-5-(4-fluoro-2- (53) G 503 1.68methylphenyl)-7-[3-(2-oxo-pyrrolidin-1-yl)-propylamino]-3,4-dihydro-1H-pyrimido[4,5- d]pyrimidin-one 1331-(2,6-Dimethylphenyl)-5-(4-fluoro-2- (53) G^(a) 447 2.76methylphenyl)-7-piperazin-1-yl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-one 134 1-(2,6-Dimethylphenyl)-5-(4-fluoro-2-(53) G 422 1.51 methylphenyl)-7-(2-hydroxyethylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-one 1351-(2,6-Dimethylphenyl)-5-(4-fluoro-2- (53) G 489 1.44methylphenyl)-7-(3-pyrrolidin-1-ylpropylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-one 1361-(2-Fluorophenyl)-5-(4-fluoro-2-methylphenyl)- (54) G 465 1.497-(2-pyrrolidin-1-yl-ethylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-one 1371-(2-Fluorophenyl)-5-(4-fluoro-2-methylphenyl)-7- (54) G 479 1.53(2-piperidin-1-yl ethylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-one 1381-(2-Fluorophenyl)-5-(4-fluoro-2-methylphenyl)- (54) H 456 1.457-(2-hydroxy-1-hydroxymethyl-1-methyl-ethylamino)-3,4-dihydro-1H-pyrimido[4,5- d]pyrimidin-one 1391-(2-Fluorophenyl)-5-(4-fluoro-2-methylphenyl)-7- (54) G 426 1.54((R)-2-hydroxy-1-methyl-ethylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-one 1401-(2-Fluorophenyl)-5-(4-fluoro-2-methylphenyl)-7- (54) G 440 1.78((S)-2-hydroxy-1-methylethylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-one 1411-(2-Fluorophenyl)-5-(4-fluoro-2-methylphenyl)- (54) H 472 1.347-(2-hydroxy-1,1-bis-hydroxymethyl-ethylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-one 1421-(2-Fluorophenyl)-5-(4-fluoro-2-methylphenyl)-7- (54) G 440 1.65(2-hydroxy-1,1-dimethyl-ethylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-one 1431-(2-Fluorophenyl)-5-(4-fluoro-2-methylphenyl)-7- (54) G 426 1.70[(2-hydroxyethyl)-methylamino]-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-one 1441-(2-Fluorophenyl)-5-(4-fluoro-2-methylphenyl)-7- (54) H 503 1.82[(racemic)-3-exo-(bicyclo[2.2.1]hept-ene-2- carboxylic acidamide)amino])-3,4-dihydro-1H- pyrimido[4,5-d]pyrimidin-one 1451-(2-Chlorophenyl)-5-(4-fluoro-2-methylphenyl)- (54) H 503 1.797-[(racemic)-3-endo-(bicyclo[2.2.1]hept-ene-2- carboxylic acidamide)amino]-3,4-dihydro-1H- pyrimido[4,5-d]pyrimidin-one 1461-(2-Fluorophenyl)-5-(4-fluoro-2-methylphenyl)- (54) G 454 1.767-[([1,3]dioxolan-2-ylmethyl)amino]-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-one 1471-(2-Fluorophenyl)-5-(4-fluoro-2-methylphenyl)- (54) G 412 1.467-(2-hydroxyethylamino)-3,4-dihydro-1H- pyrimido[4,5-d]pyrimidin-one*the sulfone product of the exemplified example number; ^(a)The reactantamine was 1-Boc-piperazine. The Boc group in this case was removedduring the reaction.

Example 1481-(2-Methylphenyl)-5-(4-fluoro-2-methylphenyl)-7-(1-ethylpiperidin-4-ylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-one

The product of example 52 (75 mg, 0.17 mmol), 1-ethylpiperidin-4-ylaminehydrochloride (100 mg, 0.5 mmol), K₂CO₃ (83 mg, 0.6 mmol) and NMP (1 mL)were combined and heated to 150° in a sealed tube for 10 h.Concentration and prep hplc afforded the title compound as an amber oil.LC MS m/z=475 (MH+), Rt=1.42 min

Example 1491-(2-Fluorophenyl)-5-(4-fluoro-2-methylphenyl)-7-(1-methylpiperidin-4-ylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-one

The product of example 54 (75 mg, 0.17 mmol),1-methylpiperidin-4-ylamine hydrochloride (94 mg, 0.5 mmol), K₂CO₃ (83mg, 0.6 mmol) and NMP (1 mL) were combined and heated to 90° in a sealedtube for 10 h. Concentration and prep hplc afforded the title compoundas an amber oil. LC MS m/z=465 (MH+), Rt=1.49 min.

The products of the examples in Table 7 are made by either the method ofexample 148 (Method I) or the method of example 149 (Method J) using thesulfone product from Table 4 as indicated and the appropriate aminehydrochloride.

TABLE 7 LC MS Example Compound name Method* m/z Rt min 1501-(2-Chlorophenyl)-5-(4-fluoro-2-methylphenyl)- (50) J 481 1.447-(1-methylpiperidin-4-ylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-one 1511-(2-Chlorophenyl)-5-(4-fluoro-2-ethylphenyl)-7- (50) I 495 1.50(1-methylpiperidin-4-ylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-one 152 1-((S)-1-Phenylethyl)-5-(4-fluoro-2-(49) J 475 1.48 methylphenyl)-7-(1-methylpiperidin-4-ylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-one 1531-((S)-1-Phenylethyl)-5-(4-fluoro-2- (49) J 436 2.20methylphenyl)-7-(1-carboxyeth-2-ylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-one 1541-((S)-1-Phenylethyl)-5-(4-fluoro-2- (49) J 449 1.64methylphenyl)-7-(1-carboxyeth-2-ylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-one 1551-Cyclohexyl-5-(4-fluoro-2-methylphenyl)-7-(1- (51) 453 1.47methylpiperidin-4-ylamino)-3,4-dihydro-1H- J^(a)pyrimido[4,5-d]pyrimidin-one 1561-Cyclohexyl-5-(4-fluoro-2-methylphenyl)-7-(1- (51) I 467 1.54ethylpiperidin-4-ylamino)-3,4-dihydro-1H- pyrimido[4,5-d]pyrimidin-one157 1-(2-Methylphenyl)-5-(4-fluoro-2-methylphenyl)- (52) J 461 1.377-(1-methylpiperidin-4-ylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-one 158 1-(2,6-Dimethylphenyl)-5-(4-fluoro-2-(53) J 475 1.42 methylphenyl)-7-(1-methylpiperidin-4-ylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-one 1591-(2,6-Dimethylphenyl)-5-(4-fluoro-2- (53) J 489 1.47methylphenyl)-7-(1-ethylpiperidin-4-ylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-one 1601-(2-Fluorophenyl)-5-(4-fluoro-2-methylphenyl)-7- (54) I 479 1.49(1-ethylpiperidin-4-ylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-one *the sulfone product of the exemplifiedexample number ^(a)The starting amine is glycine tert-butyl ester. Theester is cleaved under the reaction conditions.

Example 1611-(2,6-Difluorophenyl)-5-(4-fluoro-2-methylphenyl)-7-methoxy-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one

The product of Example 3 (0.102 g, 0.22 mmol) was suspended in MeOH (2mL) and stirred under argon. A 1 Molar solution of NaOMe in methanol(0.44 mL, 0.44 mmol) was added. After 10 min the solvent was removed invacuo, and the residue partitioned between EtOAc and H₂O. The organicphase was washed with H₂O (2×), satd aq NaCl (1×), dried over anhydrousNa₂SO₄, filtered, and evaporated to give the crude product.Recrystallization from EtOAc/hexane gave the title compound as awhite-crystalline solid. mp 210-211° C., LC MS m/z=401 (MH+) Rt=2.0 min.

Example 1621-(2,6-Difluorophenyl)-5-(4-fluoro-2-methylphenyl)-7-ethoxy-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one

The product of Example 3 (0.0658 g, 0.147 mmol) was suspended in EtOH (2mL) and stirred under argon. A 0.5 M solution of NaOEt in EtOH (0.587mL, 0.294 mmol) was added. After 15 min the solvent was removed invacuo, and the residue partitioned between EtOAc and H₂O. The organicphase was washed with H₂O (2×), satd aq NaCl (1×), dried over anhydrousNa₂SO₄, filtered, and evaporated to give the crude product. Flashchromatography on silica gel eluted with 0-5% EtOAc/CH₂Cl₂ gave thetitle compound as a white-amorphous solid. mp 191-194° C., LC MS m/z=415(MH+) Rt=2.15 min.

Example 1631-(2,6-Difluorophenyl)-5-(4-fluoro-2-methylphenyl)-7-(2-hydroxyethoxy)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one

The product of Example 3 (0.0658 g, 0.147 mmol) was suspended inethylene glycol (1 mL) and stirred under argon. NaH, dry, 95%, (8.0 mg,0.32 mmol) was added. After 30 min the solvent was removed in vacuo, andthe residue partitioned between EtOAc and H₂O. The organic phase waswashed with H₂O (2×), satd aq NaCl (1×), dried over anhydrous Na₂SO₄,filtered, and evaporated to give the crude product. Flash chromatographyon silica gel eluted with 0-10% EtOAc/CH₂Cl₂ gave the title compound asa white-amorphous solid. mp 172-175° C., LC MS m/z=431 (MH+) Rt=1.7 min.

Example 1641-(2,6-Difluorophenyl)-5-(4-fluoro-2-methylphenyl)-7-(1-methylpiperidin-4-yloxy)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-onetrifluoroacetate

A solution of 4-hydroxy-1-methylpiperidine (35.1 mg, 0.3 mmol) in DMSO(0.25 ml) was stirred under argon and NaH, dry, 95%, (7.5 mg, 0.3 mmol)was added. The mixture was stirred for 15 min, and then a solution ofthe product of Example 3 (0.0672 g, 0.15 mmol) dissolved in DMSO (0.25mL) was added. After the mixture was stirred for 30 min, the reactionmixture was partitioned between EtOAc and H₂O. The organic phase waswashed with H₂O (5×), satd aq NaCl (1×), dried over anhydrous Na₂SO₄,filtered, and evaporated to give the crude product. Purification bypreparative hplc followed by lyophillization gave the title compound asa white-amorphous solid. LC MS m/z=484 (MH+) Rt=1.47 min.

Example 1651-(2,6-Difluorophenyl)-5-(4-fluoro-2-methylphenyl)-7-[[bis-(2-hydroxyethyl)amino]ethoxy]-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-onetrifluoroacetate

NaH, dry, 95%, (8 mg, 0.4 mmol) was added to triethanolamine (243 mg,1.6 mmol), and then DMSO (0.25 ml) was added. The mixture agitated for 2min., and then the product of Example 3 (0.0896 g, 0.2 mmol) was added.After 5 min of agitation, additional DMSO (0.25 mL) was added. After themixture was agitated for 10 min, the reaction mixture was partitionedbetween EtOAc and H₂O The organic phase was washed with H₂O (5×), satdaq NaCl (1×), dried over anhydrous Na₂SO₄, filtered, and evaporated togive the crude product. Purification by preparative hplc followed bylyophillization gave the title compound as a white-amorphous solid. LCMS m/z=518 (MH+) Rt=1.25 min.

Example 166 1-(2,6-Difluorophenyl)-5-phenyl-7-methoxy-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one

Following the procedure of example 161 except using the product ofexample 45 in place of the product of example 3 gave the title compoundas a white-crystalline solid. mp 221-224° C., LC MS m/z=369 (MH+)Rt=1.92 min.

Example 1671,5-diphenyl-7-methoxy-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one a)1-(2,6-difluorophenyl)-5-phenyl-7-methylsulfonyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one

Following the procedure of example 3 except for using the product ofexample 1 in place of the product of example 2 gave the title compoundas a white solid. LC MS m/z=381 (MH+)Rt=1.78 min.

b) 1,5-diphenyl-7-methoxy-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one

Following the procedure of example 161 except using the product ofexample 167 (a) in place of the product of example 3 gave the titlecompound as a white-amorphous solid. mp 220-222° C., LC MS m/z=333 (MH+)Rt=1.94 min.

All publications, including but not limited to patents and patentapplications, cited in this specification are herein incorporated byreference as if each individual publication were specifically andindividually indicated to be incorporated by reference herein as thoughfully set forth.

The above description fully discloses the invention including preferredembodiments thereof. Modifications and improvements of the embodimentsspecifically disclosed herein are within the scope of the followingclaims. Without further elaboration, it is believed that one skilled inthe art can, using the preceding description, utilize the presentinvention to its fullest extent. Therefore, the Examples herein are tobe construed as merely illustrative and not a limitation of the scope ofthe present invention in any way. The embodiments of the invention inwhich an exclusive property or privilege is claimed are defined asfollows.

1. A process for producing a compound of Formula (IV)

wherein R₁ is an aryl ring, which ring is optionally substituted; R₂ ishydrogen, C₁₋₁₀ alkyl, C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₁₀alkyl, aryl,arylC₁₋₁₀ alkyl, heteroaryl, heteroarylC₁₋₁₀ alkyl, heterocyclic, or aheterocyclylC₁₋₁₀ alkyl moiety; and wherein each of these moieties,excluding hydrogen, are optionally substituted; R₃ is a C₁₋₁₀ alkyl,C₃₋₇ cycloalkyl, C₃₋₇cycloalkylC₁₋₁₀alkyl, aryl, arylC₁₋₁₀alkyl,heteroaryl, heteroarylC₁₋₁₀ alkyl, heterocyclic, or a heterocyclylC₁₋₁₀alkyl moiety; and wherein each of these moieties are optionallysubstituted; R_(b) is hydrogen, C₁₋₂ alkyl, NR_(c), hydroxy, thio, C₁₋₂alkoxy, or S(O)_(m)C₁₋₂ alkyl; R_(c) is hydrogen or C₁₋₂ alkyl; R_(d) ishydrogen or C₁₋₂ alkyl; X is R₂, OR₂, S(O)_(m)R₂ or (CH₂)_(n) NR₄R₁₄, or(CH₂)_(n)NR₂R₄; m is 0 or an integer having a value of 1 or 2; n is 0 oran integer having a value of 1 to 10; R₄ and R₁₄ are each independentlyselected from hydrogen, optionally substituted C₁₋₆ alkyl, optionallysubstituted aryl or an optionally substituted aryl-C₁₋₄ alkyl, or R₄ andR₁₄ together with the nitrogen which they are attached form aheterocyclic ring of 5 to 7 members which ring optionally contains anadditional heteroatom selected from oxygen, sulfur or NR₉, and whereinthe ring is optionally substituted; R₆ is hydrogen, C₁₋₁₀ alkyl, C₃₋₇cycloalkyl, heterocyclyl, heterocyclyl C₁₋₁₀alkyl, aryl, arylC₁₋₁₀alkyl, heteroaryl or a heteroarylC₁₋₁₀ alkyl moiety; and wherein each ofthese moieties, excluding hydrogen, is optionally substituted; R₉ ishydrogen, C(Z)R₆, optionally substituted C₁₋₁₀ alkyl, optionallysubstituted aryl or optionally substituted arylC₁₋₄ alkyl; Z is oxygenor sulfur; or a pharmaceutically acceptable salt thereof; which processcomprises reacting a compound of the formula

 wherein R₁ and R₃ are as defined herein for Formula (IV), and X₁ is aC₁₋₁₀ alkyl, aryl or heteroaryl moiety; under cyclization conditions toyield a compound of Formula (B):

 wherein R₁ and R₃ are as defined herein for Formula (IV), and X₁ is aC₁₋₁₀ alkyl, aryl or heteroaryl moiety; and if necessary oxidizing thesulfur moiety in S—X₁ to a sulfoxide or sulfone, and if necessarydisplacing the sulfide, sulfoxide or sulfone of Formula (B) with anucleophile selected from a primary or secondary alkylamine, arylamine,heteoarylamine, arylthiol, heteroarylthiol, alkylthiol, alkyl alcohol,aryl alcohol, heteroaryl alcohol, or a carbon nucleophile to yield acompound of Formula (IV).
 2. The process according to claim 1 wherein X₁is methyl.
 3. The process according to claim 1 wherein in a compound ofFormula (B) the sulfur in the S—X1 moiety is oxidized to a sulfoxide orsulfone.
 4. The process according to claim 1 wherein R₃ is an optionallysubstituted aryl ring.
 5. The process according to claim 4 wherein R₁and R₃ are each an optionally substituted phenyl ring.
 6. The processaccording to any claim 1 wherein the R₃ moiety is optionally substitutedone or more times independently with C₁₋₁₀ alkyl, halo-substituted C₁₋₁₀alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₇ cycloalkyl,C₃₋₇cycloalkylC₁₋₁₀ alkyl, C₅₋₇ cycloalkenyl, C₅₋₇ cycloalkenyl C₁₋₁₀alkyl, halogen, (CR₁₀R₂₀)_(n)OR₆, (CR₁₀R₂₀)_(n)SH,(CR₁₀R₂₀)_(n)S(O)_(m)R₇, (CR₁₀R₂₀)_(n)NHS(O)₂R₇, (CR₁₀R₂₀)_(n)NR₄R₁₄,(CR₁₀R₂₀)_(n)CN, (CR₁₀R₂₀)_(n) S(O)₂NR₄R₁₄, (CR₁₀R₂₀)_(n)C(Z)R₆,(CR₁₀R₂₀)_(n)OC(Z)R₆, (CR₁₀R₂₀)_(n)C(Z)OR₆, (CR₁₀R₂₀)_(n)C(Z)NR₄R₁₄,(CR₁₀R₂₀)_(n)NR₁₀C(Z)R₆, (CR₁₀R₂₀)_(n)NR₁₀C(═NR₁₀)NR₄R₁₄,(CR₁₀R₂₀)_(n)OC(Z)NR₄R₁₄, (CR₁₀R₂₀)_(n)NR₁₀C(Z)NR₄R₁₄, or(CR₁₀R₂₀)_(n)NR₁₀C(Z)OR₇, wherein R₇ is C₁₋₆alkyl, aryl, arylC₁₋₆alkyl,heterocyclic, heterocyclylC₁₋₆ alkyl, heteroaryl, or aheteroarylC₁₋₆alkyl moiety; and wherein each of these moieties may beoptionally substituted; R₄ and R₁₄ are each independently selected fromhydrogen, optionally substituted C₁₋₄ alkyl, optionally substituted arylor optionally substituted aryl-C₁₋₄ alkyl, or R₄ and R₁₄ together withthe nitrogen which they are attached form a heterocyclic ring of 5 to 7members which ring optionally contains an additional heteroatom selectedfrom oxygen, sulfur or NR₉, and which ring is optionally substituted; Zis oxygen or sulfur; R₆ is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl,heterocyclyl, heterocyclyl C₁₋₁₀alkyl, aryl, arylC₁₋₁₀ alkyl, heteroarylor heteroarylC₁₋₁₀ alkyl; and wherein each of these moieties, excludinghydrogen, may be optionally substituted; R₉ is hydrogen, C(Z)R₆,optionally substituted C₁₋₁₀ alkyl, optionally substituted aryl oroptionally substituted aryl-C₁₋₄ alkyl; n is 0 or an integer having avalue of 1 to 10; and R₁₀ and R₂₀ are each independently selected fromhydrogen or C₁₋₄ alkyl.
 7. The process according to claim 1 wherein R₃is phenyl, cyclohexyl, 2-chlorophenyl, 2,6-dimethylphenyl,2-fluorophenyl, 2-methylphenyl, or 2,6-difluorophenyl.
 8. The processaccording to claim 1 wherein R₁ is a phenyl optionally substituted oneto four times, independently, halogen, C₁₋₄ alkyl, halo-substituted C₁₋₄alkyl, cyano, nitro, (CR₁₀R₂₀)_(v)NR₄R₁₄,(CR₁₀R₂₀)_(v)C(Z)NR₄R₁₄,(CR₁₀R₂₀)_(v)C(Z)OR₈, (CR₁₀R₂₀)_(v)CORa,(CR₁₀R₂₀)_(v)C(O)H, S(O)mR₅, (CR₁₀R₂₀)_(v)OR₈, ZC(Z)R₁₁, NR₁₀C(Z)R₁₁, orNR₁₀S(O)₂R₇, and wherein Ra is C₁₋₄alkyl, halo-substituted C₁₋₄alkyl,C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₇cycloalkyl, C₅₋₇ cycloalkenyl, aryl,aryl C₁₋₄ alkyl, heteroaryl, heteroaryl C₁₋₄ alkyl, heterocyclyl,heterocyclylC₁₋₄ alkyl, (CR₁₀R₂₀)_(v)OR₇, (CR₁₀R₂₀)_(v)S(O)mR₇,(CR₁₀R₂₀)_(v)NHS(O)₂R₇, or (CR₁₀R₂₀ _(v)NR₄R₁₄, and wherein the alkyl,cycloalkyl, cycloalkenyl, aryl, arylalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, and heteroarylalkyl moieties areoptionally substituted; R₅ is hydrogen, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl or NR₄R₁₄, excluding the moieties SR₅ (wherein m is 0) beingSNR₄R₁₄, S(O)₂R₅ being SO₂H (wherein m is 2) and S(O)R₅ being SOH,(wherein m is 1); R₇ is C₁₋₆alkyl, aryl, arylC₁₋₆alkyl, heterocyclic,heterocyclylC₁₋₆ alkyl, heteroaryl, or a heteroarylC₁₋₆alkyl moiety; andwherein each of these moieties may be optionally substituted; R₈ ishydrogen, C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₃₋₇ cycloalkyl, C₅₋₇ cycloalkenyl, aryl, arylC₁₋₄ alkyl,heteroaryl, heteroarylC₁₋₄ alkyl, heterocyclyl, heterocyclylC₁₋₄ alkyl,(CR₁₀R₂₀)_(t)OR₇, (CR₁₀R₂₀)_(t)S(O)_(m)R₇, (CR₁₀R₂₀)_(t)NHS(O)₂R₇, or(CR₁₀R₂₀)_(t)NR₄R₁₄; and wherein the alkyl, cycloalkyl, cycloalkenyl,aryl, arylalkyl, heterocyclyl, heterocyclyl alkyl, heteroaryl, andheteroaryl alkyl moieties, may be optionally substituted; R₁₀ and R₂₀are each independently selected from hydrogen or C₁₋₄ alkyl; R₁₁ is C₁₋₄alkyl, halo-substituted C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₃₋₇cycloalkyl, C₅₋₇ cycloalkenyl, aryl, arylC₁₋₄ alkyl, heteroaryl,heteroarylC₁₋₄ alkyl, heterocyclyl, heterocyclylC₁₋₄ alkyl,(CR₁₀R₂₀)_(t)OR₇, (CR₁₀R₂₀)_(t)S(O)_(m)R₇, (CR₁₀R₂₀)_(t)NHS(O)₂R₇, or(CR₁₀R₂₀)_(v)NR₄R₁₄; and wherein the alkyl, cycloalkyl, cycloalkenyl,aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, andheteroaryl alkyl moieties may be optionally substituted; t is an integerhaving a value of 1 to 3; and v is 0 or an integer having a value of 1or
 2. 9. The process according to claim 1 wherein the compound ofFormula (A) is produced by reacting a compound of the formula:

wherein R₁ and R₃ are as defined in Formula (IV), and X₁ is a C₁₋₁₀alkyl, aryl or heteroaryl moiety; with a suitable reducing agent toyield a compound of Formula (A).
 10. The process according to claim 9wherein X₁ is methyl.
 11. The process according to any claim 9 whereinthe R₃ moiety is optionally substituted one or more times independentlywith C₁₋₁₀ alkyl, halo-substituted C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylC₁₋₁₀ alkyl, C₅₋₇ cycloalkenyl,C₅₋₇ cycloalkenyl C₁₋₁₀ alkyl, halogen, (CR₁₀R₂₀)_(n)OR₆,(CR₁₀R₂₀)_(n)SH, (CR₁₀R₂₀)_(n)S(O)_(m)R₇, (CR₁₀R₂₀)_(n)NHS(O)₂R₇,(CR₁₀R₂₀)_(n)NR₄R₁₄, (CR₁₀R₂₀)_(n)CN, (CR₁₀R₂₀)_(n)S(O)₂NR₄R₁₄,(CR₁₀R₂₀)_(n)C(Z)R₆, (CR₁₀R₂₀)_(n)OC(Z)R₆, (CR₁₀R₂₀)_(n)C(Z)OR₆,(CR₁₀R₂₀)_(n)C(Z)NR₄R₁₄, (CR₁₀R₂₀)_(n)NR₁₀C(Z)R₆,(CR₁₀R₂₀)_(n)NR₁₀C(═NR₁₀)NR₄R₁₄, (CR₁₀R₂₀)_(n)OC(Z)NR₄R₁₄,(CR₁₀R₂₀)_(n)NR₁₀C(Z)NR₄R₁₄, or (CR₁₀R₂₀)_(n)NR₁₀C(Z)OR₇, wherein R₇ isC₁₋₆alkyl, aryl, arylC₁₋₆alkyl, heterocyclic, heterocyclylC₁₋₆ alkyl,heteroaryl, or a heteroarylC₁₋₆alkyl moiety; and wherein each of thesemoieties may be optionally substituted; R₄ and R₁₄ are eachindependently selected from hydrogen, optionally substituted C₁₋₄ alkyl,optionally substituted aryl or optionally substituted aryl-C₁₋₄ alkyl,or R₄ and R₁₄ together with the nitrogen which they are attached form aheterocyclic ring of 5 to 7 members which ring optionally contains anadditional heteroatom selected from oxygen, sulfur or NR₉, and whichring is optionally substituted; Z is oxygen or sulfur; R₆ is hydrogen,C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, heterocyclyl, heterocyclyl C₁₋₁₀alkyl,aryl, arylC₁₋₁₀ alkyl, heteroaryl or heteroarylC₁₋₁₀ alkyl; and whereineach of these moieties, excluding hydrogen, may be optionallysubstituted; R₉ is hydrogen, C(Z)R₆, optionally substituted C₁₋₁₀ alkyl,optionally substituted aryl or optionally substituted aryl-C₁₋₄ alkyl; nis 0 or an integer having a value of 1 to 10; and R₁₀ and R₂₀ are eachindependently selected from hydrogen or C₁₋₄ alkyl.
 12. The processaccording to claim 9 wherein R₃ is a phenyl or a phenyl substituted oneor more times, independently with halogen.
 13. The process according toclaim 9 wherein R₃ is phenyl, cyclohexyl, 2-chlorophenyl,2,6-dimethylphenyl, 2-fluorophenyl, 2-methylphenyl, or2,6-difluorophenyl.
 14. The process according to claim 9 wherein thereducing agent is a hydride reducing agent.
 15. The process according toclaim 14 wherein the hydride reducing agent is lithium aluminum hydrideor NaB₂H₇.
 16. The process according to claim 15 wherein the hydridereducing agent is in an ethereal solvent, THF, Et₂O, glyme or dioxane.17. The process according to claim 9 wherein the reducing agent issamarium di-iodide in H₃PO₄, or a Raney Ni catalyzed hydrogenation, orsodium borohydride-cobaltous chloride.
 18. The process according toclaim 1 wherein the oxidation of the sulfur in the S—X₁ moiety to asulfoxide or sulfone comprises treatment of the compound of Formula (B)with an oxidant selected from meta-chloroperoxybenzoic acid, Oxone™,OsO4 and a catalytic tertiary amine N-oxide; hydrogen peroxide; peracid;oxygen; ozone; organic peroxide; potassium permanganate, zincpermanganate; potassium persulfate; or sodium hypochlorite.
 19. Theprocess according to claim 1 wherein the cyclization reaction utilizes areagent selected from carbonyl diimidazole, or a mixed anhydride; andoptionally a tertiary amine base.
 20. The process according to claim 1wherein the cyclization reaction utilizes a diamine and phosgene ortriphosgene; and a tertiary amine base.
 21. The process according toclaim 1 wherein the cyclization reaction utilitizes pyridine andcarbonyl diimidazole.
 22. A process for making a compound of Formula (C)

wherein R₁ is an aryl ring, which is optionally substituted; R₃ is aC₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇cycloalkylC₁₋₁₀alkyl, aryl,arylC₁₋₁₀alkyl, heteroaryl, heteroarylC₁₋₁₀ alkyl, heterocyclic, or aheterocyclylC₁₋₁₀alkyl moiety; and wherein each of these moieties areoptionally substituted; and X₁ is a C₁₋₁₀alkyl, aryl or heteroarylmoiety; which process comprises reacting a compound of formula 4:

wherein R3 and X1 are as defined for Formula (C) with (i) a palladiumcatalyst, and a reactant:R₁B(OH)₂  wherein R₁ is an optionally substituted aryl ring; in anorganic solvent, water and a base; or (ii) reacting a compound offormula 4 with a cross-coupling reagent selected from any arylorganozinc, aryl organocopper, aryl organotin, or an aryl organometallicreagent; or (iii) displacing the chlorine in a compound of formula 4with a nitrogen nucleophile or a sulfur nucleophile.
 23. The processaccording to claim 22 wherein the organic solvent is dioxane and thebase is Na2CO3.
 24. The process according to claim 22 wherein thepalladium catalyst is tetrakis(triphenylphophine) palladium(O).
 25. Theprocess according to claim 22 wherein X₁ is methyl.
 26. The processaccording to claim 22 wherein R₃ is phenyl, cyclohexyl, 2-chlorophenyl,2,6-dimethylphenyl, 2-fluorophenyl, 2-methylphenyl, or2,6-difluorophenyl.
 27. The process according to claim 22 wherein R₁ isan optionally substituted phenyl.
 28. The process according to claim 1wherein the sulfide, sulfoxide or sulfone of Formula (B) is displaced bya primary or secondary alkylamine to yield a compound of Formula (IV)wherein X is NR₄R₁₄, or NR₂R₄.
 29. The process according to claim 1wherein the sulfide, sulfoxide or sulfone of Formula (B) is displaced byan alkyl alcohol, aryl alcohol, or heteroaryl alcohol to yield acompound wherein X is OR₂.
 30. The process according to claim 1 whereinthe sulfide, sulfoxide or sulfone of Formula (B) is displaced by acarbon nucleophile to yield a compound of Formula (IV) wherein X is R₂.